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COPYRIGHT DEPOSIT. 



FEVER, ITS THERMOTAXIS 
AND METABOLISM 



FEVER 

ITS THERMOTAXIS AND 
METABOLISM 



BY 

ISAAC OTT, A.M., M.D. 

M 

Professor of Physiology Medico-Chirurgical College, Philadelphia, Member of 
American Physiological Society, Ex-president of American Neurological Asso- 
ciation, Consulting Neurologist Norristown Asylum, Member of the Deut- 
sche Medicinischen Gesellschaft of New York, Member of Vereinigung 
Alter Deutschen Studenten in Amerika, American Society for Phar- 
macology and Experimental Therapeutics, Society for Experi- 
mental Biology and Medicine, Member of The American 
Association for the Advancement of Science, Corre- 
sponding Member of Atlanta Academy of Medicine, 
Member of Philadelphia Medical Club and 
Chemists' Club of New York, etc. 




PAUL B. HOEBER 

67-69 E. 59TH STREET 

NEW YORK 

1914 



*& 



Copyright, 1914 
By PAUL B. HOEBER 



Published December, 1914 



Printed in U. S. A. 



MAR 13 1915 

g)CI,A397088 



Dedicated to the 

Memory of my Father, 

JACOB OTT 



"Animalia in accessibus febrium intermit- 
tentium a principio frigore et horrore cor- 
ripiunter sed paulo post majorem in modum 
incaleseunt, quod etiam faciunt a principio 
in causonibus et f ebribus pestilentialibus. ' ' 

* i Qualis vero gradus sit caloris in eerebro, 
stomacho, corde et reliquis, similiter ad hue 
non est quaesitium. ' ' Bacon, Novum Or- 
ganum. Lib. II, 13. 



PREFACE 

These three lectures were delivered be- 
fore the Sophomore Class of the Medico- 
Chirurgical College. They have been 
thought worthy of publication, as the sub- 
ject is one of maximal importance in the 
practice of medicine. The studies upon 
this subject have occupied the author for 
forty-five years, as a practitioner of medi- 
cine and a physiologist. 

Isaac Ott. 



ILLUSTRATIONS 

Fig. 1 Showing tuber cinereuin in man PAGE 

Facing page 24 

Fig. 2 Thermo-inhibitory centers in cat's brain . 37 

Fig. 3 Showing rises of temperature after injury 

to brain of man 39 

Fig. 4 Showing effect of external heat upon 
respiration when corpora striata and 
tuber cinereuin are removed . . . .58 

Fig. 5 Showing the effect of a weak faradic cur- 
rent to the tuber upon the rate of 
respiration Facing page 60 

Fig. 6 Showing the effect of a single electric 
shock to the tuber causing respiratory 
arrest Facing page 60 

Fig. 7 Showing effect of external heat upon a 

normal rabbit as regards the respiration 61 

Fig. 8 Showing effect of puncture of tuber cine- 
reuin upon blood pressure 63 

Fig. 9 Composite curve showing the average of 20 

experiments upon starved animals . . 91 

Fig. 10 Composite curve showing the average of 12 

experiments upon fevered animals . . 91 

Fig. 11 Ott's calorimeter for man 99 



ILLUSTRATIONS 

PAGE 

Fig. 12 Heat production and heat dissipation in 

malarial fever .... Facing page 118 

Fig. 13 Normal day (Lehaeheff and Avroroff from 

Ringer) 123 

Fig. 14 Day of high fever (Lehaeheff and Avroroff 

from Ringer) 129 



LECTURE I 



FEVER, ITS THERMOTAXIS 
AND METABOLISM 

LECTURE I 

(xeisttIxEmen : — In the opening course of 
physiology for this year I shall invite your 
attention to a subject which will engage 
your minds every day that you practice 
medicine. I refer to fever. In my prac- 
tice of many years it has been a daily, 
omnipresent factor. It is the alarm of the 
family, sometimes a sign of impending 
death and often a puzzle to the physician. 
The process of fever has been a difficult 
problem for the last two thousand years. 
The fever may be a gentle wave, or every 
cell may surge, boil and burn, while the vi- 
brations run to and fro until they overflow 
and the scissors of Atropos and the Styg- 
ian boat of Charon end all. 

13 



14 ISAAC OTT: FEVER 

The questions now arise, What has 
thrown a strong man into fever? Why 
has the temperature suddenly run up? 
Where is the central point of this heat 
which is like a fire in his veins ? 

The study of fever includes bacteriology, 
immunity and pathological physiology. 
Aristotle thought heat was developed in 
the right heart ; Galen placed its origin in 
the left heart, the so-called flammula 
cordis, and this was taught up to 1660. 
Bacon, in the " Novum Organum," defined 
heat as an expansive motion amongst the 
minute particles of bodies, which is the 
conclusion at which the most eminent phys- 
icists have arrived. Tyndall x quotes a 
considerable portion of Bacon's twentieth 
aphorism as illustrating the theory which 
he has himself so ably and clearly ex- 
pounded. 

In the seventeenth century, Van Hel- 
mont spoke of heat as produced in the 

i Tyndall. "Heat and Mode of Motion." Appendix. 



THERMOTAXIS AND METABOLISM 15 

heart by a mixture of sulphur and the vola- 
tile salts of the blood. 

Lavoisier, in 1775, first showed that the 
heat of animals was due to the combus- 
tion of oxygen. He also proved that the 
quantity of oxygen absorbed and of Co 2 
excreted depended upon food, work and 
temperature. In 1783, Lavoisier and La 
Place 2 made calorimetrical and respira- 
tory studies upon a guinea pig. Lavoisier 
also knew that nitrogen gas had nothing 
to do with respiration. These calorimet- 
rical studies were followed by experiments 
with a water calorimeter by Crawford 3 
and by Dulong and Von Despretz, 4 whose 
calorimeter is still a model for all subse- 
quent water calorimeters up to the present 
day. 

2 "Lavoisier et de La Place Memoire sur Chaleur." 
1780. 

s Crawford. "Experiments and Observations on Ani- 
mal Heat." London. 1788. 

4 Despretz. "Recherches experimentales sur les causes 
de chaleur animale." "Annales de Chimie et de Phy- 
sique." Tome 26; 1824. P. 337. 



16 ISAAC OTT : FEVER 

Then Begnault and Keiset, 5 in 1850, with, 
their respiration apparatus studied the 
gaseous exchanges of animals, called indi- 
rect calorimetry. Gr. A. Hirn, 6 in 1857, 
studied calorimetry of man. 

Brodie 7 held that the nervous system 
was the center of heat, whilst respiration 
cooled the animal. 

LeFevre 8 has shown that the relation 
between the amount of heat and the amount 
of oxygen is not constant. D'Arsonval 
has shown that the curves of production 
of heat and the absorption of are not 
concordant ; in sleep, for example, the pro- 
duction of heat falls to a minimum, whilst 
the consumption of oxygen is not lowered 
to a corresponding degree. 

Laulanie 9 found no fixed proportion be- 

s Regnault et Reiset. "Annales de Chimie et de Phy- 
sique." 1849. 

6 Hirn. "Recherches sur Fequivalent mecanique de la 
chaleur." Colmar. 1858. 

7 Brodie. "Philosophical Transactions." 1811. 
s LeFevre. "Chaleur animate." 1911. P. 76. 
9 Laulanie. 



THERMOTAXIS AND METABOLISM 17 

tween heat production and the respiratory 
gases exchanged. 

Then Pettenkofer and Voit 10 built their 
splendid respiration apparatus and created 
in Munich the first school for metabolism, 
which has produced many workers now 
prominent in the scientific world. 

But in the respiration calorimeter of At- 
water n and Benedict we have direct cal- 
orimetry and indirect calorimetry (or the 
gaseous exchanges) combined. Their ap- 
paratus is nearly perfect for the study of 
animal heat and by its use they have again 
verified the law of conservation of energy 
and solved many other problems in metab- 
olism. 

Hence, the three methods of studying the 
phenomena of heat are: (1) by the ther- 
mometer (probably discovered by Galileo 
and used by Sanctorius), (2) by the cal- 

io Pettenkofer und Voit. "Zeitschrift f. Biologie." 
1866. Band 11, p. 478. 
n Atwater. "A Respiration Calorimeter." 1884, 



18 ISAAC OTT : FEVER 

oximeter, and (3) by the amount of oxygen 
absorbed and the amount of Co 2 elim- 
inated (indirect calorimetry ) . 

THERMOTAXIS 

Before we take up the subject of fever, 
I will call your attention to that of thermo- 
taxis, which means heat regulation, so 
that the temperature is kept on an average 
for 24 hours at about 98.4° F. 

Now thermotaxis depends upon four 
nervous centers: two basal thermogenic 
centers — the corpus striatum and the chief 
one, the tuber cinereum — and two inhib- 
itory cerebral centers — the cruciate and 
sylvian. 

In April, 1884, 1 12 published amongst 
others the following experiments. 

Experiment 2. Babbit. Weight of ani- 
mal 7%o pounds. (Here there was a 
transverse section of the corpora striata.) 

12 Ott. Journal of 'Nervous and Mental Diseases. 
Vol. XI, No. 2, page 141, April, 1884. 



THERMOTAXIS AND METABOLISM 19 



Time P. M. 


Calorimeter Temp. 


Rectal Temp. 


12.25 


84.86 


101%° F. 


1.55 




104%° F. 


3.15 




104%° F. 


4.30 


Ri 


111%° F. 




se of 6%° F. 



Experiment 3. Cat; weight 5 x %o 
pounds; transverse section through the 
middle of the corpora striata. 

Time P. M. Calorimeter Temp. Rectal Temp. 

12.25 74.50 102%° F. 

1.40 102%° F. 

2.30 106 7 / 8 ° F. 

3.45 107%° F. 



Rise of 4%° F. 

It is from these and other experiments 
that I claim the discovery of the thermo- 
genic center in the corpus striatum. 

In October, 1884, Sachs and Aron- 
sohn 13 published a paper, six months after 

isDuBois. ArcJiiv. f. Physiologie. Oct. 31, 1884. 



20 ISAAC OTT : FEVER 

mine, stating that there was a thermogenic 
center in the corpus striatum and that it 
was located mainly in the caudate nucleus. 
They also found an increased production 
of urinary nitrogen, an increased absorp- 
tion of oxygen and an increased elimina- 
tion of carbon dioxide. The increase of 
nitrogen in the urine they inferred was 
due to a using up of the protein. They 
did not make any calorimetrical studies 
to determine positively if the increase of 
temperature was due to increased produc- 
tion of heat or to diminished dissipation. 
They offered no proof, except gaseous 
exchange and the urinary nitrogen, of 
their conclusion that the rise of temper- 
ature was due to increased production of 
heat. 

In September, 1887, Ott 14 and W. A. 
Carter (at that time a medical student) 
first showed calorimetrically that the rise 

1 4 Ott and Carter. Therapeutic Gazette. Sept. 15, 
1887. 



THERMOTAXIS AND METABOLISM 21 

of temperature after puncture of the 
corpus striatum was due to increased pro- 
duction and not to diminished dissipation 
of heat. Thus in experiment 2, in a rab- 
bit with a puncture into the right corpus 
striatum, the temperature rose 2.7° F., 
whilst heat production before the puncture 
was 13.70 B. H. units and after the punc- 
ture 22.50 heat units ; heat dissipation be- 
fore puncture was 16.68 heat units and 
after puncture 18.77 heat units. I first 
proved the existence of a thermogenic cen- 
ter in the corpus striatum and also first 
established the fact that the increase of 
temperature was due to increased produc- 
tion of heat and not to coincident dimin- 
ished dissipation. 

The claim of Richet 15 to have been the 
first to discover the thermogenic centers 
cannot be upheld. All that he claimed was 
that puncture of the anterior part of the 

is Richet. Bulletin de la Societe de Biologie. March 
29, 1884. 



22 ISAAC OTT: FEVER 

brain produced hyperthermia due to in- 
creased production of heat. 

There was no localization by him in the 
corpus striatum, but a cortical injury 
which Eulenburg and Landois before him 
had localized in the cruciate sulcus. 

Barbour, H. G., 16 has shown that the 
direct application of cold and heat to the 
region of the corpus striatum causes the 
rectal temperature to respond by a change 
in the opposite direction from that pro- 
duced in that region of the brain. Cold 
(33° C.) applied to the corpus striatum 
causes a rise in the temperature of the 
body, associated with shivering and peri- 
pheral vaso-constriction. Centrally ap- 
plied heat (42° C), on the other hand, 
causes a fall in the body temperature. 

Barbour and Wing 17 have also shown 
that the heat regulating centers are di- 

16 Archiv. f. Exp. Path, und Pharmakol. 1912. 
LXXXI. 

it Journal of Pharmacology and Experimental Thera- 
peutics, Vol. V. No. 2, p. 147. 



THERMOTAXIS AND METABOLISM 23 

rectly susceptible to the local action of 
drugs, both fever-exciting and anti- 
pyretic substances, 

Barbour and Prince i:i have shown that 

•al heating of the corpus striatum in rab- 
bits diminishes the l'o_ output, the oxygen 
combustion and the respiratory volume. 

Local cooling of the sain- region gives 
precisely the opposite results. 

Central heating reduces the tempera- 
tore of the body not only by favoring he 
dissipation but b; h - , \ 

(taction. 

TUBER CISTKRETTM 

In 1SS5, July 4, 1 1S published a prelimi- 
nary communication stating that a ther- 
mogenic center was localized at the an- 
terior end of the optic thalami, and that 
the increase of temperature after puncture 
was due to increase of production of heat. 



isott. P'. :■:.' : 5 .; -.-/_-. :ss.?. 



24 ISAAC OTT: FEVER 

as shown by the calorimeter. The tem- 
perature rise was especially marked when 
a puncture along the median line caused a 
peculiar shrill cry, a point to which Schiff 
first called attention, in the production of 
a sound. 

In March, 1887, I proved that this rise 
of temperature was due to increased pro- 
duction of heat, as shown by the calori- 
meter, and not to diminished dissipa- 
tion. 

In July, 1891, 1 19 showed that the center 
about the anterior ends of the thalami was 
more accurately located in the tuber 
cinereum. This was shown by the method 
of puncture. 

I have also punctured the tuber cinereum 
in rabbits by means of a dental drill with 
a cross bar through the mouth and obtained 
a temperature of 109°. This section does 
not cut any thermogenic fibers. 

19 Ott. Journal of Nervous and Mental Diseases. 
July, 1891. 



Tuberculosa cinereum^ 
(Hypophysis entfernt)^ 

Cofpp. mamillary 



Chiasm a 



/ X. opticus (II) 



x Tractus opticus 



Fossa interpeduncular 
s. Tarini 

Radix lateralis /&$& 

d. Tract, opticus \/X^ 
|*^ 
Radix medialis Qf? 
d. Tract, opticus* — 

Corpus geniculatum^-''' 
laterals 

Uebergang in d. Corpus y 

genie ulatum mediale 



Fasciculus obliquus. 
pontis 

Flocculus 



Plexus chorioideus 
lateralis ventriculi IV" 




^X. oculomotorius (III) 
N. trochlearis iIV) 



■N. trigeminus (V) 

-X. abducens I VI) 
-X. facialis (VII) 
"-"■——-- -NT. acusticus (Till) 

^N. glossopbaryngeus (IX) 
^N. vagus (X) 
V NN T . accessorial (XI) 



Fibrae arcuafae extt. S 
Decussatio pyramidum 



>X. hypoglossus (XII) 
*Xn. cervicales 



Fig. 1. 
Showing Tuber Cinereum in Man. 



THEEMOTAXIS AND METABOLISM 25 

Then Isenschmid and Schnitzler, 20 after 
a series of experiments, arrived at the con- 
clusion that the regulation of temperature 
was mainly in the tuber cinereum in the 
rabbit; that the fibers which run from the 
tuber lie in the caudal part of the mid- 
brain, widely distributed in the ventral and 
median part of a transverse section. In 
the anterior part of the mid-brain they 
are not united in a compact bundle. 

They also state that the corpus striatum 
is also concerned in heat regulation, but 
that it plays a subordinate part, for an 
animal without the corpora striata and 
cerebral hemispheres can regulate its tem- 
perature just as it normally does. They 
state that thermo-regulation depends 
mainly upon the tuber cinereum. 

Jacoby and Eoemer 21 have also made 

20 Isenschmid and Schnitzler. Archiv. f. Exp. Path, 
und Pharmakolog. Band 76. Heft 3 and 4. P. 202. 
1914, May. 

21 Jacoby and Roemer. Archiv. f. Exp. Path, und 
Plvarmakol. Band 70. 1912. 



26 ISAAC OTT: FEVER 

an interesting experiment by letting a 
minute globule of mercury into the third 
ventricle, which gave rise to a decided 
rise of temperature. 

Streerath 22 believes the center in the 
anterior part of the thalamus is more 
powerful than the one in the corpus 
striatum. 

J. Camus and Eoussy 23 have found that 
a lesion at the base of the brain in the 
tuber cinereum produced polyuria. Their 
experiments were made on dogs after ex- 
cision of the pituitary through the mouth. 
They state that in the tuber cinereum there 
is a zone which causes polyuria. This 
zone also has a regulating mechanism, 
which causes retention of water in the or- 
ganism. Lesions in this region are able 
to produce polyuria with parallel polydip- 
sia without disturbance of the mechanism 

22 Streerath. Archiv. f. Physiologie. 1910. P. 315. 

23 Camus and Roussy. Oomptes Rendus Societe de 
Biologie. No. 16. May 15, 1914. P. 773. 



THERMOTAXIS AND METABOLISM 27 

which causes retention of water in the sys- 
tem. In young animals it would appear 
that the regulating mechanism for the re- 
tention of water is less perfect than in 
adults. 

Furthermore of all the disturbances 
which relate to the absorptional elimina- 
tion of water, puncture at the base of the 
brain is more effective and durable than 
injections of urea, glucose, sodium chlo- 
ride, caffeine, or a watery diet. 

Bechterew and Sakovic 24 found that 
puncture of the tuber cinereum produced 
a rise of temperature and that this was 
due to increased heat production, as shown 
by Paschutin's calorimeter. 

Sakovic also showed that the carbon di- 
oxide elimination increased with the in- 
crease of temperature. Bechterew be- 
lieves that the region of the tuber cinereum 
has an undoubted influence upon the tis- 
sues of the organism. 

24 Sakovic. "Dissertation." 1897. St. Petersburg. 



28 ISAAC OTT: FEVER 

Now Isenschmid and Krehl 25 have shown 
that heat regulation was destroyed by 
making sections in the mid-brain, that is, 
when the animal was placed in a warm 
chamber it could not prevent a rise of 
bodily temperature, or, in a cold chamber, 
could not prevent a fall of temperature; 
in other words, it acted like a cold-blooded 
animal, the temperature rose and fell with 
that of the air. They arrived at the con- 
clusion that in the mid-brain a center ex- 
isted which regulated the temperature of 
the body. 

Citron and Leschke 26 found on mid- 
brain puncture that heat regulation failed, 
that cold lowered and heat elevated the 
temperature. They also found after ' i mid- 
brain puncture" that bacteria, protozoa, 
anaphylactic poison, sodium chloride, col- 
loidal paraffin, and tetrahydro-beta-naph- 

25 Isenschmid u. Krehl. Archiv. f. Exp. Path u. Phar- 
makol. Band 20, 1912. 

26 Citron and Leschke. Zeitschrift f. Exp. Path. u. 
Ther. Band 14. 1913. 



THERMOTAXIS AND METABOLISM 29 

thylamine produced no fever, but a fall of 
temperature. They believe the seat of 
pyrogenesis to be in the mid-brain. 

Cloetta and Waser 27 placed fine thermo- 
electric elements in the third ventricle. 
They also inserted thermometers in the 
rectum, in the anterior part of the cere- 
brum, under the skin and in other places. 
They then injected tetra-hydro-beta-naph- 
thylamine into the circulation. The ther- 
mometric apparatus in the third ventricle 
showed a rise of temperature in a few 
seconds, whilst in the rectum, cerebrum and 
the other parts of the body the tempera- 
ture began to rise later. Fever producing 
agents also greatly stimulated the thermo- 
genic functions of the third ventricle. 

As Isenschmid and Schnitzler have said, 
the chief nerve center in the regulation of 
heat is the tuber cinereum. It is the cen- 
ter where puncture causes rapid rise of 

27 Cloetta and Waser. Archiv. f. Exp. Path. u. Phar. 
1913. Band 73. 



30 ISAAC OTT: FEVER 

temperature, much more rapid than after 
puncture of the corpus striatum. I have 
often punctured the tuber cinereum 
through the roof of the mouth in a rabbit, 
and within four minutes produced a tem- 
perature of 110° F. A great pyretogenic 
agent, tetra-hydro-beta-naphthylamine, can 
produce fever when the corpora striata and 
the cortex cerebri have been removed, as 
I have often demonstrated. Hence the 
conclusion that the tuber cinereum is the 
ruling center in the heat regulation of 
fever. 

Cajal states that the nucleus of the in- 
ternal capsule has cells which mingle with 
the cells of the tuber cinereum. To Cajal 
the tuber cinereum is a motor station 
placed upon the projection paths of the 
septum lucidum and of other systems of 
fibers whose origin is still not determined. 

The tuber cinereum is the floor and an- 
terior wall of the third ventricle and be- 



THERMOTAXIS AND METABOLISM 31 

longs, according to Cajal, to the pars optica 
of the optic thalamus. Its posterior or ac- 
cessory nucleus resides between the mam- 
milla ry eminence and the principal nucleus 
of the tuber. The tuber also has a supe- 
rior nucleus and the fibrillary capsule on 
the surface of the nucleus hardly separates 
it from the rest of the hypothalamus. 28 

Edinger believes that the central gray 
matter of the mid-brain contains the cen- 
tral apparatus of the sympathetic. The 
afferent fibers of the mid-brain are the 
spino-tectal tracts running for all pur- 
poses in Grower's tract and ending in both 
anterior copora quadrigemina. The ef- 
ferent tract of the mid-brain is the rubro- 
spinal. Hence the tuber cinereum has four 
functions : thermogenic, polypnoeic, poly- 
uric and vaso-tonic. 

28 Cajal. "Histologic du Svst£me Xerveux." Vol. II, 
p. 48. 



32 ISAAC OTT: FEVER 

MINOR THERMOGENIC CENTERS IN THE 
SPINAL CORD 

Spinal Cord and Co 2 . 1 29 have made ex- 
periments upon cats and rabbits, using 
d'Arsonval's calorimeter and Voit's little 
respiration apparatus. After section of 
the spinal gray matter or the spinal white 
matter at the junction of the dorsal and 
lumbar regions, there was an increase of 
temperature and an increase of carbon di- 
oxide. 

Spinal Cord and Heat Production. Ott 
and Collmar 80 have shown that section of 
the lateral columns of the spinal cord in 
the cat was followed by a rise of tempera- 
ture which was accompanied by an increase 
of heat production and of heat dissipation, 
but that the increment of heat production 
was greater than that of heat dissipation. 

29 Ott. Journal of Nervous and Mental Diseases. 
Vol. XII. No. 4. October, 1885. 

30 Ott and Collmar. Journal of Nervous and Mental 
Diseases. Vol. XIV. July, 1887. 



THERMOTAXIS AND METABOLISM 33 

Spinal Cord, Its Partial Destruction, 
Effect on Heat Production, Ott, 31 in cats, 
destroyed by means of a stiff wire the 
spinal cord from the upper dorsal region 
downward; in sections and destructions 
above the fifth dorsal, heat production fell 
nearly one to two B. H. units, but after- 
wards rose to about one-third to one-half 
the normal output. If the injury was be- 
low the fifth dorsal, heat production nearly 
always remained but little below the nor- 
mal amount, and in one case exceeded the 
normal amount. In this case there could be 
no spinal thermogenic centers connected 
with the cord from the fifth dorsal down- 
ward. Whatever spinal thermogenic cen- 
ter existed must have been in the upper 
part of the spinal cord, that is, the three 
pounds of the animal, for the anterior part 
(anterior to the fifth dorsal section), fur- 

3i Ott. Transactions of Pan-American Congress. 
1893. Physiological section. 



34 ISAAC OTT: FEVER 

nished the heat. (Weight of animal was 
five pounds.) 

Now, if we assume for the sake of argu- 
ment that the heat produced after a sec- 
tion and destruction of the cord from the 
fifth dorsal is due to spinal thermogenic 
centers, with muscles and viscera, we must 
assume that the normal three pounds of 
the anterior part of the body with the 
spinal cord intact above the fifth dorsal 
vertebra can produce as much heat as the 
normal five pound animal with an intact 
nervous system. This view would be ab- 
surd. It is probable that all the heat is 
produced in the muscles and glands and 
that the spinal thermogenic centers are 
weak. 

That no thermogenic centers of a marked 
thermic capacity exist in the pons, medulla 
or spinal cord is proven by the experi- 
ment 82 of injecting tetra-hydro-beta- 
naphthylamine per jugular. ISTow this 

32 Ott. Medical Bulletin. 1898 and 1907. 



THERMOTAXIS AND METABOLISM 35 

agent is a powerful means of increasing 
the temperature to a high degree, but if 
you cut behind the tuber cinereum in a 
transverse direction, the drug is powerless 
to produce any rise of temperature. 

Dana observed a child with an absence 
of the cerebrum, thalamus and cerebellum, 
in which the temperature was normal. 
Here the tuber cinereum, vaso-motor, res- 
piratory and sweat centers took on the act 
of thermo-regulation. But I doubt if care- 
ful thermometric observations were made 
at different parts of the day in this case, 
as normal infants have a poor regulation 
of temperature. A premature infant of 6 
months and 5 days had a temperature be- 
tween 94° to 95°. 

Sternberg and Latzow 33 report a case 
of hemicephalus in which the central 
nervous system existed only as far as the 
locus coeruleus, and there was marked in- 
sufficiency of heat regulation. 

33 Bechterew. "Nerveneentra." Vol. II, p. 1198. 



36 ISAAC OTT: FEVER 

CORTICAL. THERMOTAXIO CENTERS 

Thermo-inhibitory Centers. Eulenburg 
and Landois located one in the dog at the 
cruciate sulcus. Prof. H. C. Wood 
(Senior) showed that its excision was 
followed by increased production of heat. 

I have also located a center, which is 
called the sylvian, at the posterior part 
of the cortex. The existence of this center 
has been confirmed by Dr. W. Hale White, 
in the cat. He has also shown in a man 
that a shot from a pistol, injuring the an- 
terior extremity of the middle lobe of the 
brain and also the third frontal convolu- 
tion, caused a rise of temperature, 104.4° 
F. Eoughly, this would correspond to the 
cruciate of the dog. 

Page also reported a similar case of de- 
pressed fracture of the skull, in man, 
which injured the posterior part of the 
temporo-sphenoidal lobe. This roughly 
corresponds to the sylvian. 




Fig. 2. 

Thermo-inhibitory centers in cat's brain. S, sylvian 
C, cruciate. 



37 



38 



ISAAC OTT: FEVER 



The following resume expresses my 
views of the thermotaxic centers. 

The thermotaxic centers may be classi- 
fied as follows: 

Thermogenic-tuber cinereum and 

corpus striatum. 
Minor thermogenic centers in 

spinal cord. 
Thermotaxic -\ Thermo-inhibitory, cruciate and 

sylvian. 
Thermolytic, polypnoeic in tuber 

cinereum. 
Vaso-motor and sudorific. 



THERMOTAXIC NERVES 

A thermotaxic nerve may include ther- 
mogenic, thermolytic and afferent nerves 
connected with the thermogenic centers in 
the tuber cinereum and corpus striatum, 
which are concerned with heat regulation. 

Boeke, 34 Botezat 35 and De Boer 36 have 

34Boeke. "Anatom. Anzeiger." 1913. B. 44. 

35 Botezat. "Anatom. Anzeiger." 1910. B. 35. 

36 De Boer. "Fol. Neurolog." 1913. Band 7. S. 1. 



THERMOTAXIS AND METABOLISM 39 




3 



CO ^ • 

i |s 

fa 3 



o 



40 ISAAC OTT: FEVER 

shown that every muscle fiber is supplied 
with sympathetic nerves. Hence they may 
contain heat regulating fibers. 

There are some reasons to believe that 
they run in the vagus, for immediately 
after section of the vagi heat production 
falls. There are reasons to believe that 
they also run in the sympathetic nervous 
system, and possibly in the splanchnics 
which would cause more adrenalin and 
more mobilization of glycogen and more 
glucose, which being consumed would gen- 
erate more heat. 

EFFECT OF SECTION OF VAGI UPON THE 

TEMPERATURE, HEAT PRODUCTION 

AND HEAT DISSIPATION 

1 37 have studied the effect of vagal sec- 
tion and found that the temperature gen- 
erally fell immediately and that heat pro- 
duction and heat dissipation also usually 
were diminished. 

37 Ott. Medical Bulletin. 1895. 



THERMOTAXIS AND METABOLISM 41 

Sinelnikow 38 found, after section of the 
spinal cord between the fourth and fifth 
lumbar vertebrae or in the dorsal region 
to the seventh dorsal vertebra, puncture 
into the corpus striatum caused a rise of 
temperature. But when he cut out the ac- 
tion of large bundles of muscles by resec- 
tion of the motor nerves the puncture pro- 
duced less rise of temperature. Often the 
temperature rose more in animals with ex- 
tensive paralysis than in animals able to 
move well. Hence, he infers that the punc- 
ture produces hyper-thermia but not 
through the muscular nerves. When he 
cut the spinal cord between the second and 
third dorsal vertebrae, the puncture was 
without effect. Here the visceral glands 
are in great part removed from the action 
of the thermogenic center in the corpus 
striatum. If then it is the visceral glands 
which are the chief source of heat, it be- 
comes probable that several of the ther- 

s&Archiv. f. Physiologie. 1910. P. 278. 



42 ISAAC OTT: FEVER 

motaxic nerves run in the sympathetic 
nerves. 

Hirsch and Bolly came to the conclusion 
that of the 'visceral glands, the liver was 
most important in the production of heat. 
Now the cells of the liver are supplied by 
the splanchnics, and probably they contain 
thermogenic fibers. 

Schultze 39 cut the vagus and splanchnics 
on both sides and arrived at the conclusion 
that destruction of the nervous connections 
between the brain and the large abdominal 
glands does not prevent the appearance of 
hyperthermia after a puncture in the 
corpus striatum. He infers that the hyper- 
thermia is at least not exclusively pro- 
duced by the liver and pancreas. 

These experiments show that the vagi 
and splanchnics are not the only paths for 
thermotaxic fibers, that others also descend 
in the pons, medulla and the lateral col- 

39 Archiv. f. Exp. Pathol, u. Pharmak. Band 43, p. 
190. 



THERMOTAXIS AND METABOLISM 43 

umns of the spinal cord to the muscles and 
remaining viscera. 

Ito 40 states that the warmest place in 
the body of the rabbit, after puncture, is 
in the duodenum, even when the animal has 
been without food for several days. 

Gr. Hirsch and Eolly 41 found, after 
curarization, a marked hyperthermia in 
rabbits after puncture of the brain. 

Streerath 42 found that small doses of 
strychnia caused the puncture to produce 
a higher temperature. 

All these thermotaxic and thermolytic 
centers stand in a reflex relation to the skin 
and visceral nerves, probably those of the 
hot and cold spots, in the skin and similar 
nerves in the viscera. 

Freund and E. Grafe 43 made experi- 

40 Ito. Zeitschrift f. Biologie. 1889. Band 37. 
4i Hirsch u. Eolly. Deutsches Archiv. f. Klin. Med. 
Band 75, p. 307. 1903. 

42 Streerath. Archiv. f. Physiologie. 1910. P. 295. 

43 Freund and Grafe. Archiv. f. Exp. Path. u. Phar- 
mahol. Band 70, page 135. 1912. 



44 ISAAC OTT: FEVER 

ments upon rabbits, cutting the spinal cord 
at different levels and studying the gaseous 
exchanges. After section of the dorsal 
cord the physical regulation of temperature 
was interfered with and the heat produc- 
tion was increased. In section of the 
cervical cord at 7th cervical, the heat pro- 
duction was normal, but the physical and 
chemical regulation of temperature was 
disturbed. 

By physical regulation is meant vaso- 
motor changes and the evaporation of 
sweat and the water from the lungs. By 
chemical regulation is understood a reflex 
from the skin producing increased heat 
production, increased combustion of Eub- 
ner. 

Frank and Voit 44 have shown by com- 
plete paralysis of the body in curarization, 
that the chemical regulation of the body 
heat is not lost. 

44 Frank and Voit. Zeitschrift f. Biologie. Band 24. 
N. D. 



THERMOTAXIS AND METABOLISM 45 

Dr. Bobert Meade Smith and Dr. Luk- 
janow, 45 in Ludwig's laboratory, have 
studied in detail the fatigue of the thermo- 
genic function in muscle, and also the law 
of recovery, with and without blood sup- 
ply. Each mechanism of work and produc- 
tion of heat had its own laws as regards, — 

(1) the influence of external conditions; 

(2) the influence of fatigue; 

(3) the influence of exhaustion; 

(4) the influence of temperature, and 

(5) the effect of rest and of circulating 
blood. 

As Donald MacAlister 46 has stated, the 
contractile material in muscle is not the 
same as the thermogenic. The thermo- 
genic is exhausted sooner than the contrac- 
tile. Both can be upbuilt again by the cir- 
culating blood, but the contractile in some 
cases sooner than the thermogenic. Both 

45 Du Bois.-Reymond's Archiv. 1880. 

46 "Nature of Fever." 1887. 



46 ISAAC OTT : FEVER 

metabolisms are affected by cold, but the 
thermogenic much sooner and much more 
intensely than the contractile. There is no 
fixed relation between the laws of contrac- 
tion and thermogenesis. 

Freund and Schlagintweit 47 found as a 
result of experiments upon rabbits under 
curarin, that the chemical regulation can 
functionate without motor innervation of 
the muscles. Their experiments confirm 
those of Sinelnikow 's, that during curariza- 
tion the puncture into the thermogenic cen- 
ter elevates the temperature. Infection 
could not produce fever, but sodium chlo- 
ride could generate it. 

Freund 48 after section of vagi on the 
esophagus beneath the diaphragm in rab- 
bits did not find the animals quite warm — 
their temperature stood at the lowest 
normal level. The animals were kept in a 

47 Freund and Schlagintweit. Archiv. f. Exp. Patholo- 
gie u. Pharmah. Band 71. Heft 3 and 4. P. 258. 

48 Freund. Archiv. f. Exp. Pathol, u. Pharmahol. 
Band 72, p. 295. 



THERMOTAXIS AND METABOLISM 47 

warm room, and the shaving of the ab- 
domen may have been one of the causes of 
low temperature. After longer observa- 
tion he saw no disturbance of heat regula- 
tion. The animals resisted cold and heat 
by their temperature regulation. The 
same was true when he cut the vagi in the 
neck and he doubts any inhibitory influence 
of vagi on temperature, as held by Stefani 
and Pari and also by Tscheschkow. Fever 
could also be produced with a solution 
of sodium chloride when the vagi were 
cut. 

If the vagi and splanchnics are cut the 
results are similar; the animals can also 
become feverish after injection of sodium 
chloride solution. He saw no marked ac- 
tion by vagi on chemical regulation. Sec- 
tion of both vagi beneath the diaphragm, 
combined with the high dorsal cord section 
(above the 6th segment), had an effect 
similar to that of the dorsal cord section 
combined with extirpation of both stellate 



48 ISAAC OTT: FEVER 

ganglia, or to that of the dorsal cord sec- 
tion combined with the cutting of the 8th 
cervical and 1st dorsal root. The animal 
had no heat regulation with cold or heat, 
just as after section of the cervical cord. 
After these combined sections experimental 
fever could not be produced. 

He finds it difficult to see an antagonism 
between the sympathetic and para-sympa- 
thetic system in heat phenomena. He 
states that heat regulation is in some way 
dependent on the abdominal organs. 

Ott and Scott have also made a series of 
experiments upon rabbits, dividing both 
the right vagus and right sympathetic. 
The cervical sympathetic was also excised 
from the clavicle to the superior cervical 
ganglion. The temperature was taken in 
each axilla and in the rectum at the same 
hour, at intervals of about two days for 
a month. It was always found that the 
temperature of the right axilla was from 
0.46° F. to 0.8° F. higher than that 



THBRMOTAXIS AND METABOLISM 49 

of the left. Now how is the rise of 
temperature in these experiments ex- 
plained? Temperature is maintained by 
the relation between thermogenesis and 
thermolysis. In section of the vagus 
and sympathetic we have destroyed heat 
regulation. The question arises, how has 
this been done? Have we cut vaso- 
motor fibers, thus producing an increased 
flow of blood, which would cause rise of 
temperature ? Or have we cut an afferent 
nerve of the tuber cinereum, the chief regu- 
lating center, which cannot through its ef- 
ferent nerves in the vagus and sympathetic 
control heat regulation in the right anterior 
extremity. If, however, we take those ex- 
periments in conjunction with those of 
Freund, Strassmann and Grafe where a 
section of the vagi beneath the diaphragm 
combined with section of the spinal cord 
about the upper level of the dorsal region 
destroyed chemical regulation, then we 
should infer that we have cut some of the 



50 ISAAC OTT: FEVER 

heat regulating fibers coming from the 
tuber cinereum. 

Freund 49 divided the upper half of the 
cord in the dorsal region of the rabbit and 
found that heat regulation was destroyed. 
He then punctured the corpus striatum and 
the thalami. He found that section of the 
cord up to 2nd dorsal did not hinder the 
hyperthermia of heat puncture. When the 
animals become poikilothermal, then even 
heat punctures were without effect. 

Freund and Marchand 50 found that re- 
moval of the adrenals caused a marked fall 
of temperature and a diminution of sugar 
in the blood. 

Eimden, Liithje and Liefman 51 have 
shown that in the dog with a low external 
temperature, the quantity of sugar in the 

49 Freund. Archiv. f. Exp. Pathol, u. Pharmacol. 
Band 72, page 304. 

so Freund and Marchand. Archiv. f. Exp. Pathol, u. 
Pharmakol. Band 72, page 56. 

si Eimden. Liithje u. Liefman. Hofmeister Beitrage, 
1907. B. 10. 



THEEMOTAXIS AND METABOLISM 51 

blood is regularly considerably higher ; and 
Silberstein 52 has shown on dogs that there 
is a very close relation between the quan- 
tity of sugar in the blood, the external tem- 
perature and the body temperature. In 
fever, as a rule, there is an increase in the 
quantity of sugar in the blood increases. 

Freund and Schlagintweit 53 found that 
section of the dorsal cord below the 5th seg- 
ment leaves the sugar puncture active, but 
if you cut above it there is neither gly- 
cosuria nor hyperglycaemia after the sugar 
puncture or injection of diuretin, whilst 
adrenalin produces a high hyperglycaemia. 
The section of the dorsal cord up to its 
highest segment leaves chemical regulation 
intact, which is seen in part from the rise 
of temperature after administration of 
diuretin and adrenalin. The central in- 
fluence upon the metabolism of the carbo- 

52 Silberstein. "Warmeregulation u. Zuckerstoffwech- 
sel." Kong f. inn. Med. Wiesbaden. 1913. 

53 Freund and Schlagintweit. ArcJiiv. f. Exp. Path, u, 
Pharmacol. Band 76, page 303. 



52 ISAAC OTT : FEVER 

hydrates by chemical regulation is ex- 
cluded, since the section of the splanchnics, 
as well as section of the dorsal cord above 
the 6th segment prevent the sugar punc- 
ture effect without disturbing heat regula- 
tion. 

Nebelthan 54 found that section of the 
spinal cord in the rabbit between the 6th 
and 7th cervical vertebrae produced a fall 
of temperature and that infection with ery- 
sipelas of the pig had no influence on tem- 
perature or heat production. Here the 
toxines of fever act upon the heat regula- 
tion centers, but their thermotaxic fibers, in 
great part, have been cut off. 

If the mid-brain is severed from the 
medulla, no fever can be produced, accord- 
ing to Sawadowsky. 55 

That thermotaxic fibers are concerned in 

54 Nebelthan. Zeitschrift f. Biologie. 1899. XXI, p. 
353. 

55 Sawadowsky. Centralblatt f. Med. Wissenschaft. 
1888. Band 26, p. 161, 



THERMOTAXIS AND METABOLISM 53 

chemical regulation of heat is rendered 
probable by the fact that section at the 7th 
cervical prevents a chemical regulation. 
If they were only concerned with augment- 
ing or decreasing the activity of the ponto- 
bulbar centers then chemical regulation 
should continue. It is very probable that 
about the 7th cervical and in the mid-brain 
fibers run which are concerned in thermo- 
taxis. Their pathway is probably the sym- 
pathetic and the vagus, whilst the cord 
fibers go to the muscles, and others enter 
the sympathetic ganglia and go to the cells 
of the viscera. 

That fibers may go from the tuber to the 
thermolytic centers is very probable, for in 
the tuber is a vaso-tonic, and a polypnceic 
center and fibers may extend to the sudor- 
ific centers. This is the heat dissipation 
apparatus, or physical regulation of heat. 
But there is a heat producing apparatus 
also innervating the muscles through the 



54 ISAAC OTT: FEVER 

motor nerves and the viscera by the sym- 
pathetic system. This is the chemical 
regulation of heat. 

I see no reason to assume, as some have 
done, that thermotaxic nerves do not run 
mainly in the nerves of the cerebro-spinal 
system to the muscles, but rather in the 
sympathetic. Certain fibers concerned 
with the production of heat can exist in 
motor nerves whether you hold that heat 
puncture can succeed or not in a curarized 
animal. 



LECTURE n 



LECTURE II 

Gentlemen: — To-day I shall take up 
heat dissipation or thermolysis. 

THERMOLYSIS 

This is carried on by the polypnoeic cen- 
ter in the tuber cinereum, the vaso-motor 
center, and the sudorific centers. In 1891, 
1 1 located the polypnoeic center in the 
tuber cinereum which drives the respira- 
tion center to increased activity and thus 
throws off more water from the lungs. 

Nicolaides of Athens 2 has made several 
experiments on polypnoea, and in 1910 lo- 
cated its center in the corpora striata. I 

i "Fever; Thermotaxis and Calorimetry of Malarial 
Fever." 1889. E. D. Vogel, Eastern. Pa. Also "Mod- 
ern Antipyretics." 2nd edition. 1892. E. D. Vogel. 
Easton, Pa. 

2 Nicolaides u. Dontas. Archiv. f. Physiol 1911. 
H. 3 u. 4. 249. 

57 




$ 




CM 


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58 



THERMOTAXIS AND METABOLISM 59 

have frequently cut away the corpora stri- 
ata and obtained polypnoea. The center is 
localized, not in the corpora striata, but in 
the tuber cinereum. His statement, that 
there is no polypnoea without a thermo- 
genic center, I can fully confirm, but the 
polypnoeic center is in the tuber, while the 
thermogenic centers are in the tuber and 
the corpus striatum and of these the tuber 
is the governing thermogenic center. 

Fig. 4. Shows the effect upon rabbit 
when the corpora striata and tuber ciner- 
eum are removed. As is seen, the res- 
pirations decrease instead of increasing, 
but increase somewhat at the temperature 
of 105° F., then remain about the same in 
number until about 110° F., when they 
again increase, but the rate never rose 
above the normal rate before heat was ap- 
plied. 

Fig. 5. Shows the effect of a weak 
faradic current applied to the tuber 
cinereum. When the base of the brain 



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62 ISAAC OTT: FEVER 

steam engine at high pressure." He has 
breathed rapidly ever since, and in 1892 — 
in February — the rate was 152 per minute. 
Otherwise he was in good health ; the heart, 
lungs and other organs were healthy. He 
had a tracheitis due to the rapid respira- 
tion. This case turned out to be hysterical, 
although the functional trouble must have 
been connected with the tuber, for no one 
could voluntarily keep up so rapid a rate. 

VASO-TOKIC ACTION OF TUBER CLtfEREUM 

There are also reasons to believe that 
the tuber has vaso-tonic activity, that is, 
gives tonus to the vaso-motor center. 

Fig. 8. Shows the effect of puncture of 
the tuber. The arrow represents the time 
of the lesion, the dotted line the pulse, and 
the continuous line the arterial tension. 
The tying of the animal did not cause this 
fall, as the effect of detention does not 
ensue in the first hour, which was about the 
time the observation was continued. The 



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Effect of puncture of tuber cinereum upon blood pressure. 



63 



64 ISAAC OTT: FEVER 

rate or the depth of the respirations was 
not perceptibly altered and did not influ- 
ence the arterial tension. 

This fall ensued invariably in six experi- 
ments. These observations left no doubt 
in my mind that vaso-tonic centers existed 
in the tuber cinereum. 

SUDORIFIC SECRETION 

The sudorific glands are under the con- 
trol of the sweat centers in the spinal cord, 
whose fibers, I have shown, run down the 
lateral columns of the cord. The evapo- 
ration of water from the skin carries away 
considerable heat. It is stated that a man 
who had no sweat glands by hard work 
sent his temperature up to 40-41° C. and 
his respirations became rapid. Dogs who 
have no sweat glands cool themselves off 
by polypncea, which carries off the water 
by the lungs instead of by the skin. The 
evaporation of a liter of water abstracts 
from the body 580 calories. A man will 



THERMOTAXIS AND METABOLISM 65 

lose daily about 930 calories by evapora- 
tion (about 400 calories from the water 
of the lungs and about 530 by evaporation 
of water from the skin). 

Four-fifths of heat dissipation is 
through the skin, and the quantity of heat 
dissipated is proportional to the surface 
of the skin. Rubner measured the super- 
ficial area of the body and calculated the 
metabolism per square meter of surface, 
which he calls the i ' surface area law. ' ' In 
adults, resting, Ekholm found it to be 44 
calories per square meter of surface per 
hour. Hence the metabolism of an animal 
varies approximately as its surface, and 
not as its mass. The relation of surface 
area to weight is much larger in the child 
than in the adult, and the heat production 
is proportionately larger. The relation 
of surface radiation to the development of 
fever explains the great liability of a child 
to fever. Disturbance in radiation from 
his large surface must disproportionately 



66 ISAAC OTT: FEVER 

influence the body temperature when com- 
pared with the relations in adults. Con- 
sequently a child becomes feverish very 
easily, and also becomes chilled very easily. 
Also the heat regulation centers are not 
so well regulated as in adults, hence chills 
and fever follow each other rapidly in 
children. 

Heat regulation by the heat centers, 
mainly the tuber cinereum and less by the 
corpus striatum, is also weakened in sleep; 
hence the temperature falls from this cause 
and lessened production of heat on account 
of the muscular inactivity. Heat regula- 
tion in fever is also weakened, for cold ap- 
plications have a much more marked effect 
in reducing temperature than they do in 
health. 

Dr. Eugene F. DuBois, with a Benedict 
calorimeter, found in normal controls in 
man an average production of 34.4 calories 
per hour per square meter of the body sur- 
face. 



THERMOTAXIS AND METABOLISM 6? 

Dr. Eugene F. DuBois of the Russell 
Sage Institute of Pathology, in Bellevue 
Hospital, N. Y., found with the Benedict 
respiration calorimeter that in typhoid 
fever the heat production might rise from 
100 to 160 per cent, of the normal. He also 
found that at this stage there was little or 
no specific dynamic action manifested by 
protein or carbo-hydrates, that is to say, 
the taking of food, even in large quantities, 
did not increase the amount of heat pro- 
duced. In exophthalmic goiter the total 
metabolism might rise as high as 192 per 
cent, of the normal and in cretinism it 
might be as low as 75 per cent. In all the 
various diseases studied the methods of 
direct and indirect calorimetry agreed 
closely. 

INTERNAL, SECRETIONS AND TEMPERATURE 

In Basedow's disease heat production 
is increased, probably due to excessive heat 
dissipation, as the heart is weakened, the 



68 ISAAC OTT: FEVER 

arterioles are dilated, and the blood ac- 
cumulating there gives off a considerable 
quantity of heat. 

Boldyreff found after removal of the 
whole thyroid apparatus in cats and dogs 
that there was a loss of heat regulation. 
After elevation of temperature clonic con- 
vulsions ensued. After application of cold 
the temperature fell and the convulsions 
ceased. (Boldyreff. Pflueger's Archiv. 
Band 154, page 470.) 

O. Loewi and Weselko 3 found no influ- 
ence on temperature after extirpation of 
the thyroid in rabbits. Boldyreff found 
after extirpation of the whole thyroid ap- 
paratus in cats and dogs that it was very 
defective. They found that the heat punc- 
ture in thyroidectomized animals was al- 
ways followed by a fall of temperature in 
the first hour instead of a rise as in normal 

3 Loewi u. Weselko. Zentralblatt f. Physiologie. 
1914. No. 4, page 197. 



THERMOTAXIS AND METABOLISM 69 

animals. Then it rose at best only 1.3°, 
whilst in normal animals it rose 2.5° to 3°. 
Whilst in normal animals sugar metabolism 
by the heart at the temperature increase 
was greatly increased, but in thyroidec- 
tomized animals with puncture fever, it was 
the same as in animals with thyroidectomy 
alone. 

In cretins the temperature is subnormal 
as in myxoedema, and thyroid extract 
when administered raises the temperature. 

Infundibulin (pituitrin) (hypophysin of 
Fuehner), when injected, elevates the tem- 
perature. Cushing found that when the 
pituitary was removed and the tempera- 
ture fell, an injection of the anterior part 
elevated the temperature 2-4° C. In con- 
junction with Dr. Scott I have seen the 
temperature fall to 94° F. after destruc- 
tion of the pars anterior in a monkey. Ott 
and Scott found that large doses of the 
parathyroid lowered the temperature. 



70 ISAAC OTT: FEVER 

G. Liljestrand and K. Frumerie 4 found 
the normal variations of temperature in 
fasting rabbits are much smaller than in 
animals with the usual nourishment. After 
splanchnicotomy on both sides we have an 
elevation of temperature. The heat punc- 
ture in the corpus striatum succeeds well 
— a confirmation of the observations of 
Schultze and Elias. After extirpation of 
the solar plexus and the myenteric plexus 
in rabbit, the heat puncture is as effective 
as before; there is also some diarrhoea. 
After partial extirpation of the adrenals 
the effect of the heat puncture is weakened, 
— the more so, the greater the amount of 
extirpation. After complete removal of 
the adrenals the heat puncture does not 
act. After extirpation of the adrenals in 
rabbits there is often a diarrhoea. 

Doeblin and Fleischman also removed 
the adrenals in three rabbits. In two the 

4 Skandinavisches Archiv. fur Physiologie. Band 130. 
4, 5 and 6 Heft. P. 320. 1914. 



THERMOTAXIS AND METABOLISM 71 

temperature fell after the heat puncture. 
In the third animal the temperature rose, 
but the presence of aberrant adrenal tis- 
sue was not excluded. 

In two rabbits the heat puncture was ac- 
tive when the adrenal was separated from 
the central nervous system. After extir- 
pation of the solar plexus and myenteric 
plexus in the rabbit the heat puncture was 
active. 

But the Swedish observers, Liljestrand 
and Frumerie, made many more experi- 
ments than Doeblin and Fleischman r and 
their results are to be accepted as the truth 
about the extirpation of adrenals prevent- 
ing a rise of temperature after puncture 
of corpus striatum. 

Ott and Scott 5 found in the rabbit that 
the repeated injection subcutaneously of 
5 drops of adrenalin elevated the tempera- 
ture from 103° F to 106.6° F., a rise of 3.6°. 
This was not due to more oxygen entering 

s Ott and Scott. Medical Bulletin. 1907. 



72 ISAAC OTT: FEVER 

the lungs, as Gad's aeroplethy sinograph 
showed that it reduced the volume of air 
entering the lungs. We infer it stimulates 
the thermogenic centers, because after cut- 
ting off the corpus striatum and the tuber, 
adrenalin did not in some cases cause any 
rise at all, the rectal temperature remain- 
ing the same. This rise of temperature 
was not due to diminished dissipation by 
vasoconstriction, as the temperature kept 
rising an hour and a half after the last in- 
jection of adrenalin solution. 

The fact that heat puncture does not 
succeed when the adrenals are removed 
lends support to the view advanced by Ott 
and Scott, that adrenalin is a stimulant 
of the thermogenic centers, as there is no 
rise of temperature by adrenalin injections 
after removal of the tuber cinereum. It is 
quite probable that adrenalin is needed to 
sensitize the endings of the thermogenic 
nerves, the receptive substance of cells, so 
that the thermogenic centers can act. 



THERMOTAXIS AND METABOLISM 73 

Crile 6 has shown that there is an inter- 
dependence between the brain and the ad- 
renals, that the brain cells (cerebellum in 
his experiments) show a quantitive rela- 
tion to the work changes, that the brain is 
more dependent upon the adrenals than the 
adrenals upon the brain, that the brain cells 
have a strong affinity for adrenalin. Mor- 
phine lessens the amount of adrenalin in 
the brain cells. After excision of the ad- 
renals there is a progressive loss of mus- 
cular power and a diminution of the body 
temperature. Ott and Scott have shown 
that foreign proteids injected into the cir- 
culation increase the amount of adrenalin 
in the blood, which has been confirmed by 
Crile. The fact that albumoses and pep- 
tones produce an increase of adrenalin in 
the blood may be the true cause of the 
fever in this case. Crile states that iodine 
aggravates Graves' disease and here we 

6 Kinetic System. Xew York State Journal of Medi- 
cine, May, 1914. Page 232. 



74 ISAAC OTT: FEVER 

have an increased temperature. Iodothy- 
rin and, according to Crile, thyroid ex- 
tract in large doses also cause fever; and 
Ott and Scott have shown that iodothyrin, 
iodine and thyroid extract increase the 
amount of adrenalin in the blood, con- 
firmed by Grley, as shown by the intestinal 
strip, which action of adrenalin on the in- 
testine in causing it to stop all its peris- 
taltic movements and relax was shown by 
Ott 7 in 1886. In myxoedema we have sub- 
normal temperatures. In Addison's dis- 
ease, where adrenalin is deficient, there is 
also a subnormal temperature. Morphine 
diminishes the temperature and according 
to Crile diminishes the amount of adrena- 
lin in the blood, and this lack of adrenalin 
may be one of the causes of the decrease of 
temperature by morphine. 

From all these facts I infer that adren- 
alin has a very potent activity in the in- 

7 Medical Bulletin. 1886. 



THERMOTAXIS AND METABOLISM 75 

crease of temperature when it is in excess 
in the blood. 

IS FEVER BENEFICIAL? 

Crile holds that the fever may be so fierce 
in the destruction of bacteria that the body 
itself may undergo dissolution. 

Adrenalin. Crile states that it causes 
hyperchromatism followed by chromatoly- 
sis and in over-doses destroys the cells of 
the cerebellum. When the adrenals are 
excised the Nissl substance disappears in 
a progressive manner up to death. Ad- 
renalin excites the brain and causes the 
brain to convert latent energy into heat 
and motion. 

Morphine. Crile found that under large 
doses of morphine the changes due to toxin 
of the brain cells were largely prevented. 
Thyroid and iodine have the same effect 
as infection and muscular exertion in the 
production of fever and of brain cell 



76 ISAAC OTT: FEVER 

changes. This is evidence, according to 
Crile, that certain constituents of the 
brain cells are conserved in the work per- 
formed by the brain in the production of 
fever. 

Fear causes fever in animals and Can- 
non has shown that it gives rise to the pro- 
duction of more adrenalin, which is one of 
the causes, here, of fever. Anxiety also 
causes fever, probably by excess of adren- 
alin in the blood. Crile observed an aver- 
age rise of temperature, 1%° F., in a ward 
of children as a result of a Fourth of July 
celebration. 

Crile found by the intestinal strip test 
that fear, rage, anaphylaxis after indol- 
skatol, leucine and tyrosin and the toxins 
of diphtheria, of colon bacillus, toxins of 
streptococcus, staphylococcus, foreign pro- 
teids and strychnia increase the adrena- 
lin in the blood. The test was negative 
after thyroid extract, anesthesia and 
trauma and after the injection of the juices 



THERMOTAXIS AND METABOLISM 77 

of the various organs of the same animal. 
Placental extract gave a positive reac- 
tion. After section of the splanchnics, the 
positive test by the above mentioned arti- 
cles became negative. Deep morphiniza- 
tion prevented positive results by the fore- 
going adequate agents. In brief, all the 
agents which cause hyperchromatism and 
chromatolysis gave positive results for ad- 
renalin. The one agent which protected 
the brain cells' Nissl substance was mor- 
phine. H-ion concentration test showed 
that all of the adequate stimuli giving a 
positive result in the intestinal strip test 
showed a diminution of the acidity of the 
blood from the adrenal vein. Alkalies 
cause histological changes in adrenals; 
acids do not. The adrenals activate the 
brain; the brain also activates the adren- 
als. Crile believes that the Nissl substance 
is a volatile, unstable combination of cer- 
tain elements of the brain cells and ad- 
renalin, because the brain deprived of ad- 



78 ISAAC OTT : FEVER 

renalin does not take the Nissl stain and 
the adrenals alone do not take the Nissl 
stain. 

Morphine and nitrons oxide prevent the 
consumption of the Nissl substance, prob- 
ably by preventing the oxidation of the 
brain. A combination of adrenalin, oxy- 
gen and certain brain cell constituents 
causes electric discharge that produces 
heat and motion. All of the adequate stim- 
uli with the intestinal strip reaction, after 
prolonged insomnia which affected the 
brain and the adrenal tissues also pro- 
duced identical histological changes in the 
liver cells. Hence Crile infers that the 
brain, adrenals and liver are mutually de- 
pendent upon one another for the conver- 
sion of latent into kinetic energy of heat 
and motion. In the rabbit insomnia of a 
hundred hours exhausted some of the rab- 
bits and killed others. On post mortem 
and histological studies of all the tissues 
and organs of the body, there were marked 



THERMOTAXIS AND METABOLISM 79 

histological changes in only three organs 
— the liver, the brain and the adrenals. 
These bear the stress of life ; the brain is 
the battery, the adrenals the oxidizer and 
the liver the gasoline tank and the muscles 
the furnace. The thyroid is the pace 
maker; it regulates the rate of discharge 
of energy. 

Crile states that in Graves' disease we 
find an extraordinary degree of exaggera- 
tion of the whole action of the kinetic mech- 
anism. Emotion, pain and infection pro- 
duce an exaggeration of the conversion of 
energy. In acute Graves' disease the ex- 
plosive conversion of latent energy into 
heat and motion is unequaled in any other 
disease. Feeding thyroid produces all the 
phenomena of Graves' disease except ex- 
ophthalmus and the emotional facies. 
Excessive doses of iodine alone cause most 
of the symptoms of Graves' disease. 
Hence by normal, excessive, or subnormal 
secretion of the thyroid we produce nor- 



80 ISAAC OTT: FEVER 

mal, adynamic and an excessively dynamic 
state. Defective action by the organs in 
the kinetic chain causes loss of heat, loss 
of muscular and emotional action and the 
power of combating infection. 

Overwhelming action of the kinetic sys- 
tem produces shock. The essential path- 
ology of shock is identical with its cause. 
Crile states if the brain can not endure 
the strain we have neurasthenia; if the 
thyroid can not endure the strain we 
have enlargement of it or Graves' 
disease or colloid goitre. If the ad- 
renals can not stand the strain we 
have cardio-vascular disease. If the liver 
can not endure the strain we have acidosis. 
If the liver's neutralizing effect is only par- 
tially lost, then the acidity may cause 
Bright 's disease. Excessive activity of the 
kinetic system may cause glycosuria and 
diabetes. Emotional strain, pregnancy, 
stress of business or professional life are 
all activators of the kinetic system. Hence 



THERMOTAXIS AND METABOLISM 81 

we can understand how emotions, acute or 
chronic infections may cause either Graves' 
disease or cardio-vascular disease; how 
chronic intestinal stasis with the resultant 
absorption of toxins causes cardio-vascular 
disease, neurasthenia or goiter. It also 
affords an explanation of phenomena of 
shock, whatever the cause, — toxins, infec- 
tions or foreign proteids, anaphylaxis, 
psychic stimuli or a surgical operation. 
The idea of the kinetic system has made 
possible the shockless operation, it has ex- 
plained the cause and treatment of Graves' 
disease and the control of shock and acute 
infection by overwhelming morphinization. 

HYPERTHERMIA 

Pathologists for more than a hundred 
years have held that hyperthermia in fever 
was due to an increased production of 
heat. Virchow 8 by a study of the metab- 
olism in fevers proved a greater intensity 

s Virchow. "Path. u. Ther." 1, 1854. 



82 ISAAC OTT i FEVER 

than in normal conditions, and that it was 
the cause of the hyperthermia. 

Traube 9 was the first to put forth the 
theory that hyperthermia was due to de- 
creased dissipation of heat from constric- 
tion of the arterioles due to the action of 
the toxines, and not to an increased pro- 
duction of heat. But Tscheschichin, Auer- 
bach, Wachsmuth combatted this view of 
Traube 's. 

According to Liebermeister 10 the hyper- 
thermia is due, partly to an increased pro- 
duction of heat, but especially to a change 
in the heat regulation apparatus. Ley- 
den n also supported Liebermeister in this 
view. 

Senator 12 then made some experiments 
and supported Traube in his view that the 

9 Traube. "Beitrage z. Chem. Physiol, u. Pathol." 2 
and 3. Allg. Med. Centralztg. 1863-1864. 

loHandb. d. "Pathol, u. Ther. des Fiebers." Leip- 
zig, 1875. 

ii Leyden. Deutsch. Archiv. f. Klin. Med. 536. 1869. 

12 "Untersuch ueber den fieberhaften Prozess." 1873. 



THERMOTAXIS AND METABOLISM 83 

most important factor in hyperthermia was 
the retention of heat, especially caused by 
the tetanic contraction of the peripheral 
vessels. Senator, however, believed that 
there was also an exaggeration of heat pro- 
duction, due to an increase in the combus- 
tion of the proteins, whilst the combustion 
of the carbohydrates and fats did not 
change much. 

Then we have the theory of Murri 13 that 
fever is not produced by retention of heat 
but by an increase of thermogenesis, due 
to a direct action of pyretogenic substances 
upon the cells of the organism independent 
of the nervous system. These are the 
principal theories of the second half of the 
nineteenth century. 

Babak 14 holds that the heat production 
in fever is slightly diminished. Such are 
the principal views of many observers, but 

is Murri. "Del Pot ere regolatore della temperature 
animale." Firenze, 1873. 

14 Babak. "Uebej die Waermeregulation im Fieber. 5 ' 
Archiv. f. d. ges. Physiologie. 102, 320. 1904. 



84 ISAAC OTT: FEVER 

the mass of testimony shows that there is 
an increased production of heat in fever, 
and afterwards that the heat regulation 
apparatus is reset at a higher figure, as 
Liebermeister taught. 

Porcelli-Titone 15 has made experiments 
on rabbits with a water calorimeter. He 
produced fever with 

(1) The nucleo-proteicl of plague bacil- 
lus; 

(2) Toxine of colon bacillus; 

(3) Toxine of streptococcus; 

(4) Nucleo-proteid of streptococcus; 

(5) Nucleo-proteid of typhus bacillus; 

(6) Toxine of diphtheria; 

(7) 0.85 per cent, sodium chloride solu- 
tion. 

He injected these substances into a vein 
in the ear. In the cat he used the nucleo- 
proteid of the plague bacillus and toxine 
of colon bacillus, whilst in the dog he used 

is Porcelli-Titone. "Biochemische zeitschrift." Band 
58, page 365. 1914. 



THERMOTAXIS AND METABOLISM 85 

the streptococcus and the plague bacillus. 
He used an electric motor to run the agi- 
tator to mingle the water, a method first 
used in the Ott calorimeter, in 1892. The 
error of the instrument of Titone was 0.1 
calorie. The error of Ott's little calori- 
meter for animals is 5.4 per cent, when 
tested by burning absolute alcohol. 

Titone 's results were as follows: The 
heat balance during the beginning of a 
fever is different, according to the pyreto- 
genic agent. It depends not only on the 
fever producing agent but also upon the 
kind of animal. In rabbits there is a great 
increase of heat production by the action 
of nucleo-proteids, and typhus bacillus and 
a small increase by action of sodium chlo- 
ride solution and the toxines of colon bacil- 
lus; no temperature changes ensued from 
the diphtheria toxine. The nucleo-proteid 
of streptococcus and still more the plague 
bacillus lowered thermogenesis. 

In dogs the nucleo-proteid of plague 



86 ISAAC OTT: FEVER 

bacillus caused a slight increase in heat 
production, while the streptococcus pro- 
duced a great increase. 

In cats the nucleo-proteid of the plague 
bacillus lowered heat production, while the 
toxine of the colon bacillus caused a 
marked increase. 

The estimations of the Co 2 eliminated 
confirmed the direct calorimetric data. 

As hyperthermia can be called out when 
the heat production is diminished (at times 
20%) and in other cases where the heat 
production is increased (but generally not 
beyond the physiological variations) it 
shows that there is no constant quantitive 
relation of heat production to the elevation 
of temperature. Hence Titone's hypothe- 
sis is that the greatest factor in the hyper- 
thermia of fever is diminished heat dissi- 
pation. From these data it is probable, 
he states, that the pyretogenic agent calls 
up hyperthermia by an action upon the 
heat regulation mechanism for dissipation 



THERMOTAXIS AND METABOLISM 87 

of heat, and that this is independent of the 
action upon the thermogenic apparatus. 
He believes that his experiments showed 
that the different results obtained by va- 
rious observers were due to different types 
of fever studied, and the different kinds 
of animals used. 

As to the last mentioned view, I might 
state, in man we have an increase of gas- 
eous exchange in fever (Ley den, Lieber- 
meister, Eegnar, Loewi, Kraus and 
Chvostek, Eiethus), or a decrease of gas- 
eous exchange (Wertheim, Grehant and 
Quinqaud, Riethus). While the majority 
of observers on man with a calorimeter 
found an increase of heat production 
(Liebermeister, Wahl, Hattwich, Chesno- 
coff, Leyden, Langlois), others found, like 
Traube, a diminished dissipation (C. 
Rosenthal, Maragliano, T. Rosenthal). 
Here the same animal was used, yet dif- 
ferent results were obtained. 

Temperature is the relation between 



88 ISAAC OTT: FEVER 

heat production and heat dissipation, and 
while high temperature is usually caused 
by increased production of heat, it can 
also be the result of a diminished produc- 
tion with a diminished dissipation, as I 
have found pretty frequently in my calori- 
metrical work. 

The animal may start with a normal heat 
production and heat dissipation, and the 
regulation be set lower instead of higher 
to produce a high temperature. It is quite 
probable that these exceptional cases are 
explanatory of some of the discordant re- 
sults, and not the variety of animal or 
the different toxines used, as held by 
Titone. 

The amount of Co 2 follows heat produc- 
tion, according to Titone, and if so, the 
discordant results in gaseous exchanges 
can be explained in the manner just men- 
tioned. 

As to the afebrile causes of typhoid 
fever, the setting of the heat regulation 



THERMOTAXIS AND METABOLISM 89 

apparatus at a lower level explains them 
also. 

HEAT PRODUCTION IN NORMAL AND HYPER- 
THERMIC CONDITIONS 

Dr. Wm. A. 'Carter made a series of ex- 
periments upon rabbits, cats and dogs in 
my laboratory, showing the heat produc- 
tion and heat dissipation during twenty- 
four hours, the animal being in a state of 
hunger for three days. Out of twenty 
days the maximum heat production came 
at 7 a. m. three times, at 11 a. m. twice, at 
3 p. m. five times, at 7 p. m. three times, at 
11 p. m. four times and at 3 a.m. three 
times, or ten times during the day and ten 
times at night. In experiments in which 
the same animal was used the maximum 
and minimum of heat production did not 
appear twice at the same time. There was 
no diurnal rhythm of heat production and 
of heat dissipation. There was the usual 
diurnal rise of temperature in the evening 



90 ISAAC OTT: FEVER 

(7 p. m. to 11 p. m.) and the minimum morn- 
ing temperature (7 a.m. to 11 a.m.), the 
same as has been found in man. 

In another series of experiments Carter 
used hungry animals, and the cruciate cen- 
ter of Eulenburg and Landois was de- 
stroyed, which developed a hyperthermia. 
The results showed a much greater varia- 
tion in temperature in the animal with hy- 
perthermia when compared with the nor- 
mal animal. Here it was found that heat 
production and temperature were entirely 
independent of each other. We give in 
Figs. 9 and 10 two composite curves show- 
ing the average heat production, heat dis- 
sipation and rectal temperature. The con- 
tinuous line represents heat production, 
the dotted line heat dissipation, and the 
line below shows the rectal temperature. 

PROF. WOOD'S EXPERIMENTS 

The chief work on artificial fever in this 
country has been done upon dogs by Prof. 




Fig. 9. 

Composite curve showing the average of 20 experiments 

upon starved animals. 




Fig. 10. 

Composite curve showing the average of 12 experiments 

upon fevered animals. 

91 



92 ISAAC OTT: FEVER 

H. C. Wood (Sr.) in his laboratory. 16 It 
was upon the heat production and heat dis- 
sipation in animals made feverish by the 
injection of putrid blood. He also studied 
pepsin fever in conjunction with Drs. 
Eeichert and Hare. 

Tabulation of Prof. Wood's results gives 
the following results : 

+ means increased H. P., — decreased 
H. P., compared with the second day. 



H. P. 1st fever day. 


H. 


P. 


2d fever day. 


xp. 110 + 26 






+ 31 


" 111 + 2 






+ 5 


" 112 — 6 






+ 8 


" 113 — 3 






+ 18 


" 114 






+ 37 


" 116 + 3 









An examination of Professor Wood's re- 
sults show on the first fever day an in- 
crease of H. P. in three experiments, and 

is Wood. "Fever," 1880. Smithsonian Contributions 
to Knowledge. No. 357. "Fever Thermotaxis and Cal- 
orimetry." 1889. E. D. Vogel, Easton, Pa. 



THERMOTAXIS AND METABOLISM 93 

a decrease of H. P. in two. On second 
fever day there is an increase in five ex- 
periments. 

These increments are much greater than 
those found by me, and are partly due to 
observations made at dissimilar parts of 
the clay without regard to the diurnal 
rhythm. 

My experiments upon fever were made in 
1889 upon rabbits and cats deprived of 
food for twelve hours before any observa- 
tions were made. They were carried on 
for seventy-two hours. 

The access of fever was studied during 
the first three hours and at intervals after- 
ward. It showed that after injection per 
jugular of two drops of putrid blood, the 
heat production rises rapidly and becomes 
greatest some hours before the fever curve 
attains its height. At the same time the 
curve of H. D. is lagging behind the curve 
of H. P., although following it in its up- 
ward ascent. After a while the H. P. 



94 ISAAC OTT: FEVER 

curve falls temporarily beneath the curve 
of H. D. and the temperature curve falls. 
It will be seen normally and during the 
fever in the curve of H. P. that it exhibits 
fluctuations, a fact pointed out by Senator. 
The fluctuations of H. P. are greater in 
fever. I believe the fluctuations are due 
to the action of external agencies upon the 
thermotaxic, thermogenetic and thermoly- 
tic apparatus, which are playing at see- 
saw, at one time making H. P., greater than 
H. D., at another making H. D. greater 
than H. P. 

In Exp. 1 there is an illustration of a 
high temperature, although H. P. and H. D. 
have fallen below normal of the hunger 
day or second day. In Exp. 4, we see that 
during three-fourths of the last fever day 
the temperature is below normal, and at 
the last observation H. P. is five units 
greater than those of same period on hun- 
ger day. The question arises how is Exp. 
1 to be explained? 



THERMOTAXIS AXD METABOLISM 95 

Dr. Donald MacAlister 1T has given the 
following explanation. Suppose a tall 
vessel containing water, the level of the 
water representing temperature. Let two 
pipes be connected with this vessel, one 
conveying water, the other carrying it off. 
Let the inlet and exit tubes be each pro- 
vided with a stop-cock, and let the two stop- 
cocks be connected by a rigid link which 
insures that they always turn together and 
by the same amount. If to start with, the 
inflow and outflow are equal, then however 
I move the linked stop-cocks, the height of 
the water will be the same. Xow remove 
the rigid link and connect the stop-cocks 
by a spiral spring. If now you move the 
inflow stop-cock so as to increase the flow, 
the outflow one will not at once follow, and, 
the balance being broken, the level of water 
will rise. But shortly the elasticity of the 
spring comes into activity, the outflow is 

it -Fever Thermotaxis and Calorimetry." 1SS9. E. 
D. Vogel, Eastern, Pa. 



96 ISAAC OTT: FEVER 

equal to the inflow and the rise will cease, 
but the new high level will be maintained. 
Every movement of either stop-cock will 
affect the level, which will fluctuate ac- 
cordingly, but its height at any moment 
will not be an index of the amount of in- 
flow at that, moment. The inflow may be 
slight while the level is high. If now you 
substitute H. P. for inflow and H. D. for 
outflow, and the rigid link represents the 
healthy thermotaxic mechanism, then when 
this is weakened or relaxed or broken the 
steadiness of the normal level is impos- 
sible. 

PROTEIN FEVER 

Ott and Collmar 18 studied the effect of 
albumoses and peptones upon animals. 
We discovered, in 1887, that they produced 
fever. The albumoses and peptones were 
prepared from egg albumen by Professor 

is Ott and Collmar. Journal of Physiology, Vol. VIII, 
p. 218. 1887. 



THERMOTAXIS AND METABOLISM 97 

( hittenden of Yale and were injected per 
jugular. We made experiments upon rab- 
bits and found that both albumoses and 
peptones produced fever by an increased 
production of heat, but during the first 
hour the heat production is decreased by 
the peptones, whilst the albumoses in- 
creased it during the first hour. Both usu- 
ally decreased heat dissipation during the 
first hour, which then rose with the in- 
creased production. Krehl and Matthes, 19 
in 1895, confirmed these facts. Vaughn, 20 
in 1909, demonstrated it also by the admin- 
istration of foreign protein parenterally. 

feveb iisr MAN 

Calorimetry of Malarial Fever. In my 
experiments it was brought out for the 
first time that in septic fever the heat 
production and heat dissipation may be 

19 Krehl and Matthes. Archiv. f. exp. Path. u. Pharm. 
1895, XXXV. 232. 

20 Vaughn. "Protein Split Products." P. 372. 1914. 



98 ISAAC OTT: FEVER 

diminished during the whole course of the 
fever. Usually septic fever in its in- 
itial stage is accompanied by an increased 
production of heat. Now it is easy to defi- 
nitely settle the question as to the increase 
or decrease of heat production in fever, 
and I have studied the calorimetry of ma- 
larial paroxysms during the cold, hot, and 
sweating stages. The instrument which 
I have designed is constructed as follows : 
It is composed of two cylinders of gal- 
vanized iron — one smaller than the other 
and enclosed with it (Fig. 11). The space 
in which the man lies upon a mattress is 
six feet long and two feet in diameter. 
Air is conveyed to him through the tube 
H (to which is attached at its inner end a 
coiled leaden tube through which the air 
enters the instrument), and traverses the 
whole length of the apparatus and enters 
the hollow tube of lead at P, and finally 
emerges at B, having given off its heat to 
the water between the two cylinders. The 



100 ISAAC OTT: FEVER 

meter, M, is run by the water-wheel, N, 
which aspirates the water through the 
whole apparatus by means of a hose, E, 
connecting it with the lead tube at B. The 
space between the cylinders is filled with 
about four hundred and eighty-four pounds 
of water. This water is kept thoroughly 
mixed by means of the agitator, 0, which 
has two arms. These arms are pushing 
the water back and forth thirty times a 
minute, the motion being caused by water 
running the motor, X, which, by means of 
the wheel, Z, and the eccentric, drives the 
agitator. The thermometer, A, gives the 
temperature of the water, and on account 
of the thorough mixing of the water by the 
agitator, gives the accurate record of the 
temperature of the water throughout the 
apparatus. The thermometer is pushed 
farther down than is represented in the fig- 
ure; it usually lies aside of the tube H. 
The air-tube, B, also has a thermometer 
to denote the temperature of the air as it 



THERMOTAXIS AND METABOLISM 101 

is heated up by the man. The thermom- 
eter at B is graduated into tenths, while 
the thermometer at A is graduated into 
fiftieths, but they are so far apart that one 
one-hundredth of a degree Fahrenheit can 
be read. The temperature of the mouth 
was taken by a thermometer giving tenths, 
but I expect to use one so graduated that 
I can read fiftieths. The rectal tempera- 
ture would have been preferable on account 
of accuracy. The bucket, I, receives the 
water from the motor, X, and so conveys 
it to the water-wheel, N, that it runs the 
meter as an aspirator. The meter is filled 
with water, and belongs to Voit's little res- 
piration apparatus. The quantity of air 
aspired an hour is five to six thousand 
liters, which is sufficient for respiratory 
purposes. The instrument is made air- 
tight by means of the door, K, which is 
clamped by eight powerful iron clamps. 
The inner edge of the door is lined with 
rubber. The whole apparatus is enclosed 



102 ISAAC OTT: FEVER 

in over six inches of saw-dust, the door, 
K, having against it a saw-dust mattress. 
The interior of the instrument is lighted by 
an electric light of one-candle power, by 
which a paper can be read. 

With these arrangements, excepting 
light, and a mattress inside the instrument 
I have tested the apparatus. As the ap- 
paratus necessary for the hydrogen test 
was not available, I used absolute alcohol. 
The different physicists who have burned 
a gramme of alcohol have obtained the fol- 
lowing various numbers: Thus Eumford 
obtained 6,195; DuLong, 6,962; Andrews, 
6,850; and Favre and Silbermann, 7,183.6. 
These numbers mean so many gramme- 
calories, and the number 7,183.6 is supposed 
to be the most accurate. In their experi- 
ments, in order to allow for the loss of heat 
due to radiation, a preliminary experiment 
was made with the body whose heat was 
sought, the only object of which was to as- 
certain approximately the increase of tern- 



THBRMOTAXIS AND METABOLISM 103 

perature of the cooling water. If this in- 
crease be 10°, for example, the temperature 
of the water calorimeter was reduced one- 
half this number — that is to say, 5° below 
the temperature of the atmosphere. By 
this method the water of the calorimeter 
receives as much heat from the atmosphere 
during the first part of the experiment as 
it loses by radiation during the second 
part. This procedure is called Bumford's 
compensation. In the human calorimeter 
the air tube must be of considerable size 
for the air to enter, and necessarily per- 
mits of considerable loss of heat by the air 
constantly traversing the instrument. I 
have tested my calorimeter before and 
after the performance of the experiments. 
All results by my calorimeter must have 
15.5 per cent, added to them, that they may 
be accurate. In this paper I have made 
the percentage of error 16 per cent., as the 
mean of several experiments showed this 
to be the average error of the instrument. 



104 ISAAC OTT : FEVER 

The constancy of the error made the ap- 
paratus one of precision for scientific work. 

In my experiments upon man the calcu- 
lation was made in the same manner. The 
specific heat of the body was taken to be 
0.83. 

In estimating the moisture I used Voit's 
little respiration apparatus, taking the 
moisture of the air of the room and deduct- 
ing it from the moisture of the air coming 
from the calorimeter. Now, according to 
Helmholtz, 1,000 grammes of water require 
582 calories in evaporation from the lungs 
and skin. 

The glass bulbs were filled partly with 
sulphuric acid, and weighed upon a delicate 
balance before and after the absorption of 
moisture from the air. 

By placing a pulley outside the calori- 
meter and attaching to a leather rope a 
fourteen pound weight, the man within the 
instrument was able to exercise. The 
leather band entered one of the air holes 



THERMOTAXIS AND METABOLISM 105 

of the instrument. In this manner it was 
found : 1. That a man weighing one hun- 
dred and ninety-two pounds, during the 
afternoon produced 410 heat units per 
hour on an average and not 512 as calcu- 
lated by oxidation changes and the amount 
of egesta. 2. Of the whole amount of heat 
dissipated, about 14 per cent, is thrown off 
by the lungs. 3. The elevation of about 
five tons an hour a foot high doubles the 
hourly heat production. 

The study of the calorimetry of malarial 
fever has never been attempted, except by 
a study of the changes in the leg or arm. 
Langiois attempted by an air calorimeter 
to study the heat production in pneumonia 
of children, but the instrument is by its 
construction so inaccurate, that it will give 
only very gross changes. 

The instrument used in the study of the 
malarial paroxysm is accurate in its 
workings as has been already detailed. 
Through the great kindness of Dr. J. F. 



106 ISAAC OTT: FEVER 

Berg, of Plainfield, N. J., I was able to 
study upon the person of Mr. W. W. 
Schenk, the first accurate calorimetry of 

malarial paroxysms. Mr. S was 5 feet 

9y 2 inches in height, aged twenty-nine, a 
farmer, and the chill he had was the fourth 
one. During the course of this tertian in- 
termittent fever, he was taking no medi- 
cine. He ate a very light breakfast at 
7.30 a. m. At 8 a. m. his temperature was 
98, at 9.30 a. m., 99.2, felt catching pains 
in the nape of the neck; at 10.18 a. m., he 
entered the calorimeter, temperature 100.1. 
While in the calorimeter he had chills run- 
ning up and down his back, his hands felt 
cold, and he had a general sense of chilli- 
ness. Upon leaving the instrument, 11.18 
a. m., his pulse was 84, temperature, 101.85 ; 
10.35 a. m v thirsty, feels badly, looks pale, 
bones and head ache, has a pinched and 
anxious look; pulse 92. At 11.47 a.m., 
again entered the calorimeter, tempera- 
ture, 101.4, left instrument at 12.48 p. m., 



THERMOTAXIS AND METABOLISM 107 

temperature, 102.0; pulse, 112; complains 
of heat while in instrument, face flushed, 
hands moist. At 1.15 p. m. ate a fair din- 
ner. At 1.40 p. m., pulse 84; temperature, 
100.6; headache, face flushed, some per- 
spiration. 2 p. m., temperature, 100.2, 
entered calorimeter; 3 p.m., left it, pulse, 
84; inside of calorimeter moist from per- 
spiration, he noted the musty odor for the 
first time in the instrument. 8 p. m., tem- 
perature, 98.2; feels quite good; had four 
movements of bowels, supposed to be due 
to water not accustomed to. 

Second day. — 7.30 a. m., ate a good break- 
fast, entered calorimeter at 9.53 a. m., tem- 
perature 99.0; left instrument at 10.53 
a. m., temperature, 99%; pulse, 84; at 11.22 
a. m., entered calorimeter, temperature, 
99.25. At 12.22 p. m., left it, temperature, 
99.25; had another movement of bowels, 
took a whisky before dining at 1 p. m. 

At 1.35 p. m., again entered the calori- 
meter, temperature, 99.2; left it at 2.35 



108 ISAAC OTT : FEVER 

p. m., temperature, 99.7 ; pulse, 92 ; felt 
good, and left for home on Saturday. 

On following Sunday had a light chill. 
No chills since. One week since the last 
chill he again entered the calorimeter for a 
test of his normal heat production. He 
was well, and ate heartily. On the prev- 
ious day he was engaged in very laborious 
work. 

By means of the electric light (which 
gives a very uniform heat) of one candle 
power, he was able to read the morning 
news while his heat production was being 
taken. It was found by burning absolute 
alcohol, that with the electric light, the er- 
ror was 2.8 per cent, which was to be de- 
ducted from the amount of heat production 
registered by the calorimeter. 

From a study of Fig. 12 it is found that 
during the initial stage or chill-period of 
a malarial paroxysm, the dissipation is not 
as great as at other times, and the heat 
production is enormously increased. After 



THERMOTAXIS AND METABOLISM 109 

the fever reached its height, the previous 
great rise of heat production was suc- 
ceeded by a great fall, according to the law 
of compensation. Here high temperature 
is not an index of a correspondingly high 
production of heat. 

In the stage of defervescence, heat dis- 
sipation is greatly increased and heat pro- 
duction does not regain its original height. 
It is only during the sweating stage that 
the excess of moisture comes over in the 
sulphuric acid bulbs on the fever-day. If 
the heat production on the chill day and on 
the succeeding day is compared with that 
of the normal day, it will be found to be 
on the chill-day 79.3 heat units in excess, 
and on the succeeding day 9.6 heat units in 
deficit. This is a much greater increase 
than that seen in the septic fever of ani- 
mals. 

These observations show how fever in 
man is originated, that is, usually heat pro- 
duction runs rapidly ahead of heat dissi- 



110 ISAAC OTT: FEVER 

pation, which is partly lessened, and the 
temperature is elevated. On the next day 
after the malarial paroxysm there was a 
slight fever, and the heat production on the 
average was lower than on the preceding 
day. 

There is. every reason to believe that in 
a continued fever this increase of heat pro- 
duction does not usually last many days, 
but that the fever continues because of an 
altered relation between heat production 
and heat dissipation, without regard to an 
increased or diminished heat production. 
These observations confirm a modified 
theory of Liebermeister's. The theory of 
Traube, that fever causes a vaso-motor 
spasm ; that of Marey, that a vaso-paraly- 
sis exists; or the more recent view of 
Rosenthal, that of heat retention — all these 
theories contain only a germ of truth, that 
is, during the chill and fever there is a 
lessened dissipation of heat when compared 
with the sweating stage. Appended are 



THERMOTAXIS AND METABOLISM 111 

the calorimetrical results upon which Fig. 
12 is founded. 

"chill" day. 

A. T. = Air temperature. 
C. T. — Calorimeter temperature. 
E. T. = Temperature of exit air tube. 
M. T. = Temperature of mouth tube. 
Litres = Amount of air aspirated through the calori- 
meter. 

A.M. A.T. C.T. E.T. M.T. Meter 

10.18 73.3 67.70 20.6 101.1 Litres 51.37 

11.18 72.8 68.38 21.1 101.85 Weight 138 9/50 





.68 


.75 






H. D. = 369.1 


H.P. 


= 569.8 


A. M. 


A. T. C. T. E. T. 


M.T. 


Meter 


11.47 


73.1 68.36 21 


101.85 


Litres 50.40 


12.47 


74.0 69.01 21.6 


102.00 


Weight 137 29/50 



+.65 .15 

H. D. = 354.0 H. P. == 371.1 

P. M. Meter 

2 75.3 68.95 21.6 100.2 Litres 47.92 

3 73.9 69.57 21.8 100.6 Weight 138 40/50 

+ .62 

H. D. =3 373.1 H. P.= 419.2 



112 ISAAC OTT : FEVER 



DAY AFTER THE CHILL. 



A.M. 


A.T. 


C. T. E. T. 


M. T. 


Meter 


9.53 


73.7 


69.14 21.2 


99.0 


Litres 54.53 


10.53 


75.3 


69.69 22.2 
.55 


99.4 


Weight 136 40/50 




.4 






H.D 


. = 355.4 


H.P, 


. = 400.8 


A.M. 


A. T. 


C. T. E. T. 


M.T. 


Meter 


11.22 


74.3 


69.68 21.8 


99.25 


Litres 51.50 


12.22 


75.2 


70.29 22.2 
.61 


99.25 


Weight 136 31/50 










H.D 


. = 335.8 


H.P. 


= 335.8 


P.M. 








Meter 


1.35 


77.8 


70.22 22.2 


99.2 


Litres 52.15 


2.35 


75.8 


71.75 22.4 
.53 


99.7 


Weight 137 44/50 




.5 






H.D 


. = 338.7 


H.P. 


= 395.9 


NORMAL DAY ONE WEEK 


AFTER HE HAD A CHILL 


A.M. 


A.T. 


C. T. E. T. 


M.T. 


Meter 


11.06 


71.0 


65.60 19.0 


98.05 


Litres 52.51 


12.06 


72.2 


66.20 20.2 
.60 


98.85 


Weight 138.58 




.80 






H.D. 


= 373.8 


H.P. 


= 414.0 



THERMOTAXIS AND METABOLISM 113 

P.M. A.T. C.T. E. T. M.T. Meter 

12,24 72.2 66.16 20.0 98.85 Litres 50.04 

1.24 72.0 67.78 20.4 98.85 Weight 138.44 



.62 

H. D. =:342.88 As no electric light, add 16% = 54.86 
H.D. = 397.74 

H. P. = 397.74 No moisture came over. 

P.M. 

2.35 73.4 66.86 20.6 98.5 Litres 48.73 

3.35 74.1 67.34 21.0 99.4 Weight 140.12 



.48 .9 

H. D.=: 264.82 No electric light, add 16% = 42.37 
H. D. = 307.19 
H. P. = 411.19 No moisture came over. 

Through the great kindness of Dr. F. G. 
Benedict of the Carnegie Nutrition Labora- 
tory, I have obtained a translation of a 
paper 21 upon the heat phenomena in ma- 
larial fever, which confirms my researches 

21 A. A. Lichacheff and P. P. Avroroff. "Investiga- 
tions of Gaseous and Heat exchange in Fevers. (Febris 
intermittens tertian.)" A separate reprint from volume 
V, parts 3 and 4. Reports of the Imperial Military 
Medical Academy. St. Petersburg. Printing office of 
M. Merusbera, Nevski prospect 8, 1902. 



114 ISAAC OTT: FEVER 

made ten years previous to theirs. As it 
is rather inaccessible to many of us I shall 
give you an abstract of considerable extent. 



LECTURE III 



LECTURE III 

Gextlemex. — In this lecture I shall con- 
tinue the study of malarial fever and the 
metabolism. 

Their investigations were made with a 
water calorimeter of Professor Paschutin, 
and at the same time they measured the 
gaseous exchanges. (The calorimeter is 
described by Lichacheff. Heat production 
in a healthy person when in relative rest. 
Dissertation, St. Petersburg, 1S93. A 
description of calorimeter of Paschutin.) 

The calorimeter was oval in form, about 
3 yards in length and the same in height, 
with a capacity for air of about 2.7 cubic 
meters. In this space is a metallic net in- 
stead of a floor, with, a bed consisting of 
a rubber mattress and pillow inflated with 
air. For sitting a bench is placed in the 

117 



118 ISAAC OTT: FEVER 

chamber and the person can make two to 
three steps. The chamber can be closed 
hermetically by two covers (one inside the 
other, in which are two glass windows). 
The ventilation is by a special suction air- 
pump, which is operated by a gas motor, 
and can suck out 150 liters of air in a min- 
ute. The ventilation was ordinarily 80 
liters in a minute, or about 5 cubic meters 
of air an hour. The air entering the cham- 
ber was first deprived of Co 2 and water by 
absorption by potash and concentrated sul- 
phuric acid. The air coming out of the 
chamber was conveyed through sulphuric 
acid and potash. There was an electric 
light in the chamber, of one candle power, 
and its heat estimated. The temperature 
of the apparatus ranged from 17-20 C. 

For signaling purposes there was a bell 
and for talking a speaking tube which was 
divided by a thin impenetrable gauze or 
cover of natural rubber. 

Before beginning the experiment, they 



THERMOTAXIS AND METABOLISM 119 

weighed the food, the jars of urine, feces, 
the linen wear, the clothes and bed of the 
sick one. The moisture of air in the ap- 
paratus was determined with the aid of a 
psychrometer. The patient was weighed 
and immediately placed in the apparatus. 
After closing the covers of the calorimeter, 
which required about half an hour, the 
ventilating air would be admitted into the 
chamber and the stirring of the water in 
the calorimeter was commenced for the 
purpose of reading an even temperature in 
the apparatus. However, the calorimeter 
determination would begin, not at once, but 
an hour or more later, with the object that 
during that time it would settle itself to 
the well-known more or less constant rela- 
tionship between the temperature of the 
apparatus and the temperature of the sur- 
rounding moist conditions, which are to be 
observed in reaching a high degree of pre- 
cision in the indications of the apparatus. 
In order to obtain the results as to the in- 



120 ISAAC OTT: FEVER 

tensity of heat production and exchange 
of matter during different moments of the 
fever attack, the test of the whole 24 hours 
was broken up into separate periods, each 
continuing 2 hours, thus we had 11 periods 
of 2 hours each. At the end of each period 
she would have a change of temperature 
during % hour, and we would record the 
readings of all the thermometers of the 
apparatus (calorimeter, as well as under 
the skin, and that of the room). For a 
still more accurate observation we re- 
corded the thermometers not only at the 
end of two hour periods, but also in the 
middle of it, that is, we would make records 
each hour, also the temperature of the pa- 
tient (a woman during the fever attack) 
was measured each hour. 

The patient, Anastasia Zarerski, was 17 
years old, weighing 49.321 kilograms. The 
fever was a tertian intermittent. They 
made observations during the attack of 
fever on May 12 and May 14, and a third 



THERMOTAXIS AND METABOLISM 121 

series of observations during the time of 
absence of fever on May 18-19, that is, 4 
days after the last fever attack. After 
May 15 and 16, she received quinine. Her 
maximum temperature was, at 6 p. m., 
36.7° C, and minimum, at 11 p. m., 36° C. 
During the rest of the night and day the 
temperature kept within the limits of 
36.2°-36.6°. 

HEAT PRODUCTION 

Heat production in the evening hours at 
the beginning of the observation stood at 
about 85 kilo-calories per hour, then it be- 
gan to fall quite rapidly and by 5-7 in the 
morning it reached its minimum, which was 
about y 2 the quantity of the evening fig- 
ures — ±6 calories per hour. This con- 
siderable reduction of heat production 
within the organism coincided with the 
time of sleep of Miss Zarerski. During 
morning hours heat production would 
somewhat increase and stood at a height 



122 ISAAC OTT: FEVER 

of 70-65 calories per hour, and in the after- 
noon, from 3 to 5 p. m., it increased still 
more, up to 77 calories. Just as in the 
evening 1 hours we observed a maximum of 
heat production, so we also had a maxi- 
mum temperature in normal healthy men. 
She normally had 32 calories per kilo of 
weight. 

HEAT LOSS 

The absolute amount of heat loss was 
maximum 91 calories per hour from 7 to 
9 in evening, minimum, 53 calories, from 
5 to 7 in the morning. During the day- 
time heat loss was 60-70 calories per 
hour. 

The heat lost by radiation and conduc- 
tion was determined by noting the changes 
in the temperature of the calorimeter and 
the changes in the temperature of the air 
that passed through it. The heat lost by 
evaporation of water was measured by de- 
termining the quantity of water given off 



7P.M. 9 11 1A.M. 3 5 7 9 11 1P.M. 3 5 



38 




















































r 




















































6i 


















































' TEMPERATURE 


36 






































































































90 


CAL 


9RII 


















































s 












































80 








\ 


\ 


i 






































A HEAT PRODUCTION 










\\ 


































/ 


A 




70 






( 


^ 






































fj 


B 


B TOTAL MEAT 










k 








\, 




















A 






// 


/ 




ELIMINATION 


CO 










N 


k 








^ 


> 


















\ 


^ 


V 






























\ 




/i 




















>c_ 


C MEAT LOSS THROUGH 


50 




























'/ 


i 


K 














/ 


RADIATION & CONDUCTION 


























\ 


( 


/ 




**> 


r - * 


--< 


*'*-. 


"••■s 


/ 








40 


















\ 


*-*. 








> 
















































~-i 


\ 
























30 




































































































D HEAT LOSS DUE TO 


20 




«_ 












































•u 


EVAPORATION OF WATER 


10 


























=*=■< 


>■"«*= 










































































40 






































































































35 






































































































10 














































/ 


» H 


I O GIVEN OFF THROUGH 




















































LUNGS 4. SKIN. 


25 










— 


\ 










r** 
























» r 














N 


, 








i 




























20 














V 






^L 




y 










































































15 


„ 



















































Fig. 13. 
Normal day (Lehacheff and Avroroff from Ringer). 



123 



124 ISAAC OTT: FEVER 

by the patient through her skin and lungs, 
and multiplying the same by 0.59 calories. 
The total heat production was obtained 
from the sum of the values of heat lost by 
evaporation of water and by radiation and 
conduction, plus or minus the retention 
or loss of heat because of changes in the 
body temperature. This last one was de- 
termined from the formula: W X (T ± 
t) X S. W equals body weight, T equals 
temperature of the body, t equals value of 
change of temperature, and S equals spe- 
cific heat of body, which equals 0.83. The 
patient was in the calorimeter for 3 days 
— one normal and two fever days. The 
results are seen in Figs. 13 and 14. 

HEAT LOSS BY RADIATION AND EVAPORATION 

Of the total sum of heat losses, the share 
of heat loss by radiation and heat conduc- 
tion is 1.104 calories, or 74.6%, and the 
share of heat loss by evaporation is 376 
calories, or 25.4%. 



THERMOTAXIS AND METABOLISM 125 

GASEOUS EXCHANGE 

The elimination of Co 2 followed approx- 
imately the same order as did the develop- 
ment and loss of heat within the organism, 
namely, during evening hours, 7 to 11, the 
elimination of Co 2 stood at the maximum 
height, 26.5 grams per hour, then during 
the night (early morning) hours it fell to 
18 grams and during the day hours an 
average of about 25 grams per hour. The 
night minimum of elimination of Co 2 was 
reached earlier than heat production and 
heat loss of the organism, so that at this 
time when the development of heat within 
the organism still continued to lower, the 
elimination of Co 2 already started on its 
rise. 

WATERY VAPOR 

Watery vapor, maximum 33 grams per 
hour in the night, it gradually came down 
to its minimum, 24.5 grams, and then dur- 
ing the morning hours would rise up to its 



126 ISAAC OTT: FEVER 

former height. The amount of absorbed 
oxygen during 22 hours was equal to 406 
grams, and the respiratory quotient was 
0,92. 

The amount of N eliminated in the urine 
during 24 hours was equal to 11.4 grams. 
During fever days, Miss Zarerski ate but 
little (incomplete hunger) and she lost 
weight. 

FEVER OBSERVATIONS 

The stage of increase of fever was five 
hours and the period of decrease of fever 
about five hours. The chill commenced at 
2 a. m. The temperature normally was 
36.1°, and then rose to 37.9° and then to 
39.3°, and at 7 p. m., was 39.7°, when the 
chill stopped. Then the temperature fell 
to normal by 11 o'clock, and from 11 to 12 
the fever was over. The duration of the 
whole attack was about 10 hours. The pe- 
riod of the chill was about 3 hours. 

Heat Production. During the period of 



THEKMOTAXIS AND METABOLISM 127 

12-2 a. m., when there was no fever, and 
the patient in complete rest, there were 54 
calories per hour. From 2-4 a. m., when 
patient was also asleep and woke up 14 of 
an hour earlier than before, for she was 
disturbed out of her sleep for the purpose 
of taking the temperature, the heat pro- 
duction rose to 93 calories per hour, which 
coincided with the chill and rise of tem- 
perature, or the first stage of the fever. 
From 4-5 a. m., heat production rose to the 
maximum 112 calories, and the tempera- 
ture rose to 39°, and the chill continued. 
During the succeeding 2 hours, from 5-7, 
heat production fell to 75-80 calories. 
After 7, the temperature began to fall and 
heat production at the same time fell to 56 
calories; when sweat appeared, 8 to 10 
a. m., the heat production gave a second 
wave, reaching 88 calories per hour, and 
then came down to its original level. 

We see that heat production of our first 
observation in fever stands, until the be- 



128 ISAAC OTT: FEVER 

ginning of the attack and a few hours after 
the end of the attack, is lower than normal, 
owing to the diet. During the fever attack 
and immediately after the curve of heat 
production stands all the time higher than 
normal. 

Heat production of the patient during 
the whole fever attack was considerably 
higher and the increase comes, almost with- 
out exception, from the period of rise of 
temperature. 

General Heat Loss. From 12 to 2 a. m., 
when the patient slept, it stood at 65 cal- 
ories per hour. During the following 2 
hours, when the chill began, with a rise of 
temperature the heat loss was somewhat 
decreased, but not much, coming down to 
56 calories. From 4-7 heat loss stood at 
its original level, although the tempera- 
ture during that time reached 39.7°. After 
this temperature had reached its maxi- 
mum, the heat loss began to rise quite 
rapidly, and by 8 reached 77, and by 9 



12P.M. 2A.M. 4 6 6 10 12 2P.M. 4 6 8 10 




TEMPERATURE 

A HEAT PRO0OCTI0M 
B TOTAL MEATL0S9 

C HEAT L083 THROUGH 
RADIATION £ CONOUCTIOM 



D HEAT LOSS DUE TO 
EVAPORATION OF WATER 



H2 GIVEN OFF THROUGH 
LUNGS 4 SKIN. 



?2 GIVEN OFF 



Fig. 14. 

Day of high fever (Lehacheff and Avroroff from 

Ringer). 

129 



130 ISAAC OTT: FEVER 

a. m., was up to 112 calories, double the 
original height. From 9 to 10, heat loss 
stood at the same height and by 2 o'clock 
it fell to 71 calories. Prom 2 to 6 p. m., it 
rose to 84 calories per hour, and after 8 
p. m., when the patient was asleep, it came 
down to 60 calories, at about which level it 
stood at the very beginning of the observa- 
tion. 

Comparing the curve of heat loss with 
normal curve of heat loss, we see at the be- 
ginning of the fever attack, from 12-2 a. m., 
that heat loss stood at quite the same level 
as normal, and that during the first half 
of the attack, that is, during the rise of 
temperature of patient, the heat loss was 
somewhat higher than normal, since the 
curve of the normal day during these night 
hours coinciding with the time of sleep no- 
ticeably fell. During the second half of 
the attack, during the fall of temperature, 
the heat production rose much above nor- 



THERMOTAXIS AND METABOLISM 131 

mal, exceeding it almost one and a half 
times. 

If we compare the curve of heat loss 
with the curve of heat production for the 
same fever day, we find both curves in their 
appearance are quite alike to each other; 
both during the fever have a quite sharp, 
but not lasting ascent, then a rapid fall and 
during the evening hours they rise again. 
But the differences in the curves are as 
follows : the curve of heat production dur- 
ing the fever attack gives but one wave, 
whilst heat dissipation curve gives at least 
two, from which the second wave, the one 
much lower in height, comes during the 
second half of the attack. The wave in the 
heat production curve, in time of appear- 
ance, precedes the same wave in the curve 
of heat dissipation by about 5 hours. The 
increase of heat production occurs at the 
very beginning of the attack, at the time of 
rapid rise of temperature, but the increase 



132 ISAAC OTT: FEVER 

of heat dissipation is observed only in the 
second half of the attack, during the fall 
of fever temperature and the fall of heat 
production which by that time succeeds in 
coming down to normal and gives a second 
rise coinciding in time with the appearance 
of the principal wave of heat loss. 

In the increment of temperature the de- 
crease of heat dissipation either played no 
part at all or played a very insignificant 
part. Here the rise of temperature in the 
patient was owing to the increased develop- 
ment of heat in the body, and the decrease 
of it was conditional upon an increased 
heat dissipation during the second half of 
the attack. 

Heat Loss by Evaporation of Water 
from Skin and Lungs. It was higher than 
normal during the whole 24 hours. Dur- 
ing the night and morning the heat loss by 
evaporation was 20 calories per hour, and 
in the afternoon about 24 calories. From 
8 to 10 a. m., it rose from 20 to 29 per 



THERMOTAXIS AND METABOLISM 133 

hour, and after 10 hours it fell to 22 cal- 
ories. The maximum of heat loss coin- 
cided with the appearance of sweat. The 
minimum heat loss by evaporation from 
skin and lungs was 19-20 calories per hour, 
coincided and took place from 2-6 a. m., 
that is, just during the period of chill. 

Gaseous Exchange. Before the fever 
attack, during sleep, the elimination of Co 2 
stood at a very low quantity, 20 grams per 
hour. Then with the rise of temperature 
and heat production, the elimination of Co 2 
began to rise noticeably and gradually 
rose to 34 grams, which coincides in time 
with the highest point of temperature from 
6 to 8 a. m., though heat production fell by 
this time considerably. With the fall of 
temperature during the second half of the 
attack, the elimination of Co 2 rapidly di- 
minished too, and only in the afternoon 
showed, like the heat production, a tem- 
porary increase. There was a parallel in 
the curves between heat production and 



134 ISAAC OTT: FEVER 

the elimination of Co 2 ; a similar state was 
also seen normally. There was no corre- 
spondence between the curve of elimina- 
tion of Co 2 and that of heat dissipation. 

Absorbed Oxygen. The amount of oxy- 
gen absorbed for 22 hours was equal to 
563 grams and the respiratory quotient 
was 0.75. The absorption of oxygen in 
fever was higher compared with the nor- 
mal in an average for 22 hours. 

Nitrogen. The amount of N eliminated 
with the urine during the 24 hours was 10.2 
grams less than normal. 

Their general deductions (after the sec- 
ond experiment with the same patient), 
were as follows : 

Max. For 22 hours 

Temp. H.P. Co 2 Ho 2 2 R.A. 

Normal ..36.0 — 36.6(C) 1.48 calories. 513 637 406 0.92 

Mild fever 
2nd ob- 
servation 37.9 1.492 " 520 638 474 0.80 

Severe 
fever 1st 
observa- 
tion ...35.8 — 39.7 1.633 " 587 852 563 0.76 

In both observations, during the whole 
fever period there was observed a distinct 



THERMOTAXIS AND METABOLISM 135 

increase of both heat production and heat 
loss, and the increase of heat production 
occurred almost without exception during 
the rise of temperature and an increase of 
heat dissipation occurred during the pe- 
riod of decline of temperature. 

In both of their fever observations there 
was a distinct rise of gaseous exchange; 
the increase of elimination of Co 2 was 
mainly during the period of rise of tem- 
perature and the elimination of water was 
sharply raised during the period of fall of 
temperature. 

They also made experiments upon them- 
selves while working under normal condi- 
tions. The mechanical labor consisted in 
lifting a weight of one pound (about 36 
lbs.) standing upon a stool at a height of 
60 centimeters, and letting it down to the 
floor for 2 hours after a previous rest of 
2 hours, then a rest of 4 hours. 

They found that under physiological 
conditions the organism can considerably 



136 ISAAC OTT : FEVER 

increase within itself the production of 
heat without causing thereby any sub- 
stantial rise of its own temperature. 
Hence, they infer that the fever rise of 
temperature in a strictly physical sense 
depends chiefly upon the rise of heat pro- 
duction. From a physiological point of 
view we see in this fact that a very sub- 
stantial part is undoubtedly played by the 
thermo-regulating facilities of the organ- 
ism. 

METABOLISM IN FEVEiR 

Hirsch and Miiller have shown that as 
the liver has the highest temperature, the 
greater metabolic changes must be found 
in this organ. The question then arose, 
whether after puncture of the thermogenic 
centers in animals freed of glycogen there 
ensued an elevation of temperature. Eolly 
found that in twenty-one rabbits with no 
glycogen in the muscles or liver, puncture 
of the thermogenic center did not cause an 



THERMOTAXIS AND METABOLISM 137 

elevation of temperature. In two rabbits 
only was there a rise of 0.4 and of 0.2° 
Fahrenheit. To animals free of glycogen 
he fed simple sirup to produce glycogen 
again ; puncture of the brain then produced 
fever. In glycogen-free animals the injec- 
tion of bacteria (pneumococcus and bac- 
terium coli) produced a fever; hence in 
glycogen-free animals infection generates 
fever, but in the same animal thermogenic 
puncture does not. 

Eolly also found that albumoses and pep- 
tones do not generate fever in glycogen- 
free animals. Ott * proved that they gen- 
erated fever in animals in normal condi- 
tion. 

Eolly also found that there was no in- 
crease (or only a small one) of urinary 
nitrogen after thermogenic puncture in gly- 
cogen-free animals. Hence Eolly supports 
Krehl and Schultz in their theory that the 
small increase of urinary nitrogen after 

i Jour, of Physiol., 1887, VIII, 218. 



138 ISAAC OTT: FEVER 

brain puncture is due to the hyperthermia 
and is not a direct result of the puncture 
of the thermogenic center. In the glyco- 
gen-free animals not only does the thermo- 
genic puncture produce no fever, but the 
increase of urinary nitrogen does not take 
place to any extent. Eolly believes that 
in neurogenic fever the increase of urinary 
nitrogen is due to the hyperthermia and 
not to the irritation of the thermogenic 
nerves. The greater increase of urinary 
nitrogen in fever generated by bacteria is 
due to an increased destruction of protein 
produced by the infection itself. In infec- 
tious fever there is from the beginning an 
abnormal destruction of proteid. 

Hirsch, Miiller and Eolly hold to the 
theory that in fever we have two parallel 
processes: (1) a specific breaking up of 
the proteid by the bacteria, and (2) a cen- 
tral excitation in the sense of a neurogenic 
fever. 



THERMOTAXIS AND METABOLISM 139 

Aronsohn has opposed this view. He 
believes that the increased destruction of 
proteid is dependent upon the nerves and 
ferments. The theory of a toxic destruc- 
tion of proteid is without foundation. An 
increased destruction of proteid ensues ac- 
cording to him (1) where there is a paucity 
of glycogen and fats; (2) in toxic fever 
and in excessive irritation of the nerves, 
and (3) in cachexias. The increased de- 
struction of proteid, according to Aron- 
sohn, is a result of the fever-process due to 
heightened innervation of the cells — an ir- 
ritation of a thermogenic center. 

Senator and Richter (1) found results 
differing from those of Hirsch, Miiller and 
Roily. They also, by means of strychnia, 
made animals free of glycogen, and then 
made a puncture into a heat center, corpus 
striatum, which was followed by a tempera- 
ture nearly as high as in animals with gly- 
cogen. They inferred that glycogen was 



140 ISAAC OTT : FEVER 

not necessary to the generation of fever 
and no special substance was needed to pro- 
duce hyperthermia. 

Ott and Scott 2 have studied the effect 
of an agent, tetra-hydro-beta-naphthyla- 
mine, upon glycogen-free animals. This 
body is a pure nervous agent in the pro- 
duction of fever. One of us has in another 
place 3 shown that it acts only when the 
corpus striatum and tuber cinereum are 
present, If only the corpora striata are 
removed, still the irritations of the thermo- 
genic centers in the tuber by it are sufficient 
to produce a fever. 

We did not find it an easy matter to free 
the animal completely of glycogen, but we 
had some with complete absence of glyco- 
gen either in the liver or muscles. 

We showed that tetra-hydro-beta-naph- 
thylamine will produce fever in a glycogen- 

2 Ott and Scott. Journal of Experimental Medicine, 
Vol. IX, No. 6, 1907. 

3 Ott. Medical Bulletin. 1898. XX. 411. 



THERMOTAXIS AND METABOLISM 141 

free animal. The fever here must be due 
to a using up of the protein. The metab- 
olism of the protein is set into activity 
by the stimulation of the thermogenic cen- 
ters in the corpus striatum and the tuber 
cinereum, for the removal of these cen- 
ters prevents the naphthylamine from 
causing a rise of temperature. 

Naphthylamine is a powerful thermo- 
genic stimulant like the poisons of infec- 
tious fevers. Here the naphthylamine 
stimulates the nerve centers to act upon 
the protein, initiating changes in it. These 
facts do not support the views of Krehl 
and Eolly that puncture of the brain acts 
only on glycogen, while the infectious 
fevers produce a toxic metabolism of pro- 
tein. 

Nearly all observers agree that in fever 
there is an increased protein metabolism, 
but no increased fat metabolism except 
such as may result from inanition in the 
individual. There is everv reason to be- 



142 ISAAC OTT : FEVER 

lieve that in both puncture of the thermo- 
genic centers and in the infectious fevers, 
fever is produced by an action on the ther- 
mogenic centers. 

BIBLIOGRAPHY 

Aronsohn. — Allgemeine Fieberlehre, 1906; Zeit. 

f. Bin. Med., 1907, LXXVIII, 153. 
Lush.— "The Science of Nutrition," 1906. 
Roily. — Dent. Archiv f. Min. Med., 1903, 

LXXVIII, 250. 

PROTEIN METABOLISM 

Dr. Lusk, from 250 experiments upon 
dogs, in speaking of the specific dynamic 
action of food stuffs, found that the 
cause of it lay not in the absorptive or ex- 
cretive mechanisms but in the interplay be- 
tween the living cells and the nutrient ma- 
terial, the sugars and amino-acids in the 
blood. There was a marked increase in 
heat production after the ingestion of 
sugar, but in the 4 to 5 hours the heat pro- 
duction regained the level of basal metab- 



THERMOTAXIS AND METABOLISM 143 

olism. He believes the cause of this in- 
creased heat production to be due to the 
mass action of the sugar molecules reacting 
upon the liver cells. When alcohol was 
added to the glucose the heat production 
was raised above the level to which glucose 
alone would have raised it, and the alco- 
hol was oxidized in preference to the carbo- 
hydrates. Lusk also studied three amino- 
acids convertible into sugar and urea and 
found that they could be given without 
appreciable increase of heat production. 
The result that followed the administration 
of amino-acids was like that which occurred 
after meat ingestion, in that the amount 
of increase of heat production was pro- 
portional to the quantity metabolized. He 
holds the view that the great increase in 
heat production is due to stimulation of 
the protoplasm to higher activity through 
the mass action of accumulated amino- 
acids. He also believes that the highest 
heat production is coincident with the 



144 ISAAC OTT : FEVER 

highest metabolism of ammo-acids, and 
that the ammo-acids themselves do not lie 
in the tissues to act as stimuli without be- 
ing involved in highly active metabolism. 
It was shown that specific intermediary 
acids were formed in metabolism. These 
were the real stimuli, and when ingested 
protein was reconstructed into body pro- 
tein the amino-acids involved in this re- 
action did not cause an increase in heat 
production. It might be stated that living 
cells metabolized carbo-hydrates and fats 
in increased quantity when these were 
present in large amounts in the surround- 
ing fluid, and that they were also stimulated 
to a higher heat production during metab- 
olism of certain amino-acids to an extent 
entirely out of proportion to their energy 
value. 4 

High temperature by itself increases the 
metabolism of proteins. Pflueger has es- 
timated that for every increase of 1 degree 

*Med. Record. 1914. June 27. P. 1189. 



THERMOTAXIS AND METABOLISM 145 

C in a rabbit's temperature, the beat pro- 
duction increases about 6 per cent., and tbe 
same bas been found to be true for man 
wben subjected to artificial beat. But this 
is only one cause of tbe increased produc- 
tion of beat in bypertbermia. 

The infectious fevers bave an increased 
nitrogenous metabolism. In an animal in 
starvation an equilibrium of metabolism 
is easily obtained. The nitrogen in tbe 
urine readily gives the amount of protein 
consumed, and albumen administered by 
the mouth easily keeps up a nitrogen bal- 
ance. 

In May's experiments upon rabbits the 
nitrogen after intravenous injection of a 
broth of bacillus of swine erysipelas, the 
temperature was 39.5 and nitrogen output 
1.79; on the fourth day the temperature 
was 41.2° C. and nitrogen output 1.81; and 
on the fifth day it was 41.2 to 40.7, nitrogen 
output 2.45 grams. 

In Staehlin's experiments dogs were in- 



146 ISAAC OTT: FEVER 

oculated subcutaneously with the trypan- 
osome of Surra. The animal was in a con- 
dition of nitrogen equilibrium ; it was kept 
in the Pettenkofer respiration apparatus 
and the output of nitrogen, carbon and 
water determined. He also made calori- 
metrical valuations of the food, urine and 
feces. Muscular work was avoided. 

During the 1st fever day the dog took 
all his food, yet the outgo of nitrogen ex- 
ceeded the in-go by a considerable amount. 
From the 4th to 7th day of the fever, the 
output of nitrogen was 44% above the ni- 
trogen of the ingesta. From the 7th day to 
the 10th day, the output of nitrogen was 
higher than in the normal period, although 
the amount of food was diminished, and 
from the 10th to 12th days — the terminal 
days — the nitrogen deficit was on the 10th 
day 7.1 grams, and then diminished to one- 
half this amount. According to these 
figures the animal lost about 20% the orig- 
inal nitrogen present in the body. 



THERMOTAXIS AND METABOLISM 147 

Sharpe and Simon 5 found in a case of 
malaria that there was a tendency for the 
rise of temperature to be accompanied by 
an increased output of total nitrogen and 
less uniformly of creatinine. In two dogs, 
in whom the fever was preceded by rigor, 
the output of uric acid was increased. 

Shaffer 6 has shown that the giving of 
large amounts of carbo-hydrates on a low 
protein diet may completely, or almost 
completely, maintain the patient in nitro- 
gen balance throughout the disease. 

There is no parallelism between the 
amount of nitrogen in the urine and the 
temperature of the body. Pribram and 
Eobitschek and subsequently Fiirbringer 
and Zuelzer found that the elimination of 
sulphur to a certain extent ran parallel 
with the variable urinary nitrogen. 

Salkowsky further found that the in- 

5 Sharpe and Simon. Journal of Experimental Medi- 
cine, Vol. XX. No. 3, p. 282. 

6 Shaffer. Journal Am. Med. Association, 1908, Vol. 
51, p. 974. 



148 ISAAC OTT: FEVER 

creased outgo of nitrogen was accompanied 
also by an increased elimination of potash 
salts. 

Leathes also found in hospital patients 
that the creatinine was increased in fever. 
Linsen and Schmid found the purin bodies, 
ammonia and amino-acids, increased. 

Graham and Poulton 7 by means of 
a chamber of heated steam elevated their 
temperature to 104° F., but notwithstand- 
ing the temperature there was no increase 
of metabolism by the high temperature. 

Shaffer and Coleman 8 found that in ty- 
phoid fever, with an abundant diet of fat 
and carbohydrates, there was a nitrogenous 
equilibrium with a low intake of protein. 

Kocher 9 has shown that a very liberal 
diet of as much as 80 calories per kilogram 
did not retard the protein metabolism of 

7 Graham and Poulton. Quarterly Journal Med., Oct., 
1912, p. 8. 

s Shaffer and Coleman. Archiv. Int. Med. 1908, p. 
538. 

» Kocher. Archiv f. KUn. Med. 1914. CXV. 82. 



THERMOTAXIS AND METABOLISM 149 

typhoid fever in the early period of ty- 
phoid, as they did later. He holds that the 
protein destruction is due to the action of 
a special toxic substance upon protoplasm. 

Coleman 10 has also found that food does 
not increase the heat production or tem- 
perature in typhoid fever, even when given 
in large amounts, at least where the quan- 
tity of protein is kept relatively low. A 
liberal diet in fever will not raise the tem- 
perature. He also found that just as in 
health, the body uses carbohydrates in 
preference to fat or protein to meet the in- 
creased demand for energy in typhoid 
fever. This teaches the necessity of a pre- 
dominance of carbohydrates in the diet of 
a typhoid fever patient. 

Causes of Protein Destruction. It is 
not alone increased temperature but also 
a toxic destruction of protein which in- 
creases the metabolism of protein in fever. 

!o Coleman. Journal Am. Med. Association. Vol. 
LXIII. No. 4. 1914. P. 932. 



150 ISAAC OTT: FEVER 

The intracellular ferments also act upon 
the increased amount of amino-acids and 
break them up and thus produce an in- 
creased elimination of nitrogen. 

OAKBO-HYDRATE METABOLISM 

It was found out by May and Weber 
that the breaking up of protein may be 
reduced by giving carbo-hydrates. Hence 
it is probable that with the increased de- 
struction of protein in fever, the glycogen 
also undergoes consumption at the same 
time. All the glycogen is consumed in the 
first few days of fever, and thus partially 
increases heat production. 

METABOLISM OF FATS 

The fats like the glycogen are also at- 
tacked in fever, but preferably the glyco- 
gen. Experiments lead to the idea that 
the gradual wasting of the fat is not due 
to any direct action on the fats, but rather 
to partial hunger. Staehelin does not be- 



THERMOTAXIS AND METABOLISM 151 

lieve that the using up of fat is entirely 
due to partial starvation. 

WATER METABOLISM 

In fever, conduction and perspiration- 
evaporation are lessened ; the functions of 
dissipation do not act to maintain equili- 
brium at the same level, whether produc- 
tion of heat is normally increased or de- 
creased. The continuous vaso-constric- 
tion reduces conduction and radiation of 
heat from the skin. The cause of fever, 
vaso-constriction, proceeds from the in- 
terior. The perspiration is lessened, and 
here we have another source of diminished 
radiation of heat. The water from the 
lungs is not diminished in fever. 

Schwenkenbecker and Inagaki u show 
that insensible perspiration in fever is as 
great as in health, and that there is no ac- 
cumulation of water in the body, as held 

11 Schwenkenbecker u. Inagaki. Archiv. f. Exp. Path, 
u. Pharmakol. 1906. B. 54, p. 168. 



152 ISAAC OTT: FEVER 

by Von Leyden. However, the urine is 
decreased in quantity. 

Lang 12 has shown that the elimination 
of sweat is diminished during the eleva- 
tion of temperature in man, but becomes 
normal at the height of the fever, whilst 
in some cases there is increased evapora- 
tion from the lungs. 

In Staehilin's dog infected with surra, 
the total intake of water was 9030, whilst 
the total outgo was 11225, making an in- 
crease of 21955, or calculated by metabol- 
ism, 1880. There was certainly no reten- 
tion of water here. 

Von Noorden states that in fever the or- 
ganism eliminates by the lungs more 
water, even during fasting, than a healthy 
individual does after a meal ; the augmen- 
tation amounts to about 50%. The in- 
crease is, however, small. 

12 Lang. Archiv. f. Klin. Med. 1903. Band 79, p. 
343. 



THERMOTAXIS AND METABOLISM 153 

PUKIN METABOLISM 

It was shown by Erben that xanthin 
bodies and animo-acids are increased in 
fever but in a degree varying with the 
character of the disease. 

A. R. Mandel 13 found in so-called aseptic 
or surgical fevers that there is a large in- 
crease of the purin bases in the urine of 
patients fed with milk. The temperature 
rises and falls with the quantity of purin 
bases eliminated. Mandel also showed 
that subcutaneous injection of 40 milli- 
grams of xanthin caused a marked rise in 
the temperature of a monkey, and that a 
strong decoction of 60 grams of coffee 
caused slight fever in a man not used to 
it. 

Ott and Scott 14 found guanin, adenin 
and hypo-xanthin caused an elevation of 

1 3 Mandel. American Journal of Physiology. 1904. 
Vol. X, p. 452. 

14 Ott and Scott. The Medical Bulletin. Oct., 1907. 



154 ISAAC OTT: FEVER 

temperature in rabbits, whilst uric acid 
did not. 

ACETONE BODIES AND ACIDS IN FEVER 

Beta-oxybutyric acid, diacetic acid and 
acetone have been found in the urine of 
patients with increased temperature, but 
of the three bodies acetone is more fre- 
quently present. 

It was noted by Eegnard and Greffert 
and also by Minkowski and Kraus that the 
amount of carbon dioxide in venous blood 
was diminished. It was supposed to be 
due to increased formation of acid in the 
body. Ammonia was also increased, and 
it would lead us to think that there was an 
acid poisoning. 

CHLORIDES AND PHOSPHATES IN FEVER 

Eedtenbacher first noted a retention of 
chlorides in the body, and this has been 
confirmed by several observers. 

In pneumonia it was found that the 



THERMOTAXIS AND METABOLISM 155 

amount of sodium chloride in the urine 
was very greatly diminished before the 
crisis. After the crisis, it is excreted to 
a considerable extent. Von Limbeck, 
Schwarz, Von der Berg and Moraczewski 
regard the chloride excretion as inversely 
proportional to that of phosphoric acid, 
that retention of chlorine takes place in 
consequence of increased phosphoric acid 
elimination, the retained chloride keep- 
ing up an isotonic condition in the 
blood. 

Fever consists of at least two main 
characters — thermogenic and toxogenic. 
As to the temperature, there is an agent 
which deranges the harmony of the ther- 
mo-inhibitory, thermogenic and thermo- 
lytic apparatuses, by which in the initial 
stage the metabolism of the tissues is 
usually temporarily increased and this in- 
crement is usually greater than that gen- 
ated upon a restricted amount of nutri- 
ment. It is during the chill that heat 



156 ISAAC OTT: FEVER 

dissipation is temporarily diminished, but 
afterwards it usually follows the fluctua- 
tions of heat production. The tuber 
cinereum and the corpus striatum play 
the most important part in the thermo- 
genic process and of these two the tuber 
is more important. Neither increased 
production nor diminished dissipation are 
necessary to constitute fever, as is shown 
where heat production diminished al- 
though the temperature is elevated. In 
another experiment of mine on lower ani- 
mals, at one period the temperature was 
subnormal, yet the heat production was 
greatly increased above that seen on a 
similar period of the preceding day. As 
to the other symptoms in fever, they are 
caused by the toxines, chemical substances 
affecting every cell. 

The toxines stimulate the cells causing 
increased metabolic change and consump- 
tion of energy. Hence the true theory of 
fever is a neurotoxogenic process. 



THERMOTAXIS AND METABOLISM 157 

That there is no increased production 
of heat in the stages of continued fever, 
but only a disarranged regulation of heat 
is quite evident to anyone who has stood 
by the bedside of a typhoid fever case in 
its terminal stages, with a high tempera- 
ture, when the body looks more like a 
cadaver than like a living being throbbing 
with the fullness of blood and life. To 
imagine, despite the paucity of food, the 
wasting of the cells of the muscles and 
of the viscera, the fever is due to in- 
creased production of heat is ridiculous. 

IS FEVER NOXIOUS OR BENEFICIAL ? 

It has been shown by Roily and Melt- 
zer 15 and Luedke 16 that animals heated 
up to 40°, after receiving daily subcutane- 
ous injection of one-fourth to one-half the 
fatal dose of either staphylococci, pneumo- 

15 Roily and Meltzer. Deutsch. ArcMv. f. Klin. Med. 
1908. XCIV. 335. 

is Luedke. Deutsch. Archiv. f. Klin, Med. 1909. 
XCV. 425. 



158 ISAAC OTT: FEVER 

cocci or bacilli coli communis, lived longer, 
and one-half of them survived, whilst all 
the control animals died. 



INDEX OF AUTHOES 

Cushing, 69 



Andrews, 102 
Aronsolm, 19, 139, 142 
d'Arsonval, 16, 32 
At water, 17 
Auerbach, 82 
Avroroff, P. P., 113 

Babak, 83 

Barbour, H. G., 22, 23 
Bechterew, 27 
Benedict, F. G., 17, 113 
Berg, J. F., 106 
Boeke, 38 
Boldyreff, 68 
Botezat, 38 
Brodie, 16 

Cajal, 30 
Camus, J., 26 
Cannon, 76 
Carter, W. A., 20, 89 
Chesnocoff, 87 
Chvostek, 87 
Citron, 28 
Cloetta, 29 
Coleman, 148, 149 
Collmar, 32, 96 
Crawford, 15 

Crile, 73, 74, 75, 76, 77, 
78,. 79, 80 

159 



Dana, 35 
De Boer, 38 
Despretz, 15 
Doeblin, 70, 71 
DuBois, Eugene, 66, 67, 
Dulong, 15, 102 

Edinger, 31 
Eimden, 50 
Ekholm, 65 
Elias, 70 
Erben. 153 
Eulenburg, 22, 36, 90 

Favre, 102 

Fleischman, 70, 71 

Frank, 44 

Freund, 43, 46, 49, 50, 51 

Frumerie, K., 70, 71 

Fiirbringer, 147 

Galileo, 17 
Geffert, 154 
Gley, 74 
Graham, 148 
Grafe, E., 43, 49 
Grehant, 87 



160 



INDEX OF AUTHOKS 



Hare, 92 
Hattwich, 87 
Helmholtz, 104 
Hirn, G. A., 16 
Hirsch, 42, 43, 136, 138 

Inagaki, 151 
Isenschmid, 25, 28, 29 
Ito, 43 

Jacoby, 25 

Kocher, 148 

Kraus, 87, 154 

Krehl, 28, 97, 137, 141 



MacAlister, Donald, 45, 95 
Mandel, A. K., 153 
Maragliano, 87 
Marchand, 50 
Marey, 110 
Matthes, 97 
May, 145, 150 
Meltzer, 157 
Minkowski, 154 
Moraczewski,155 
Muller, 136, 138 
Murri, 83 

Nebelthan, 52 
Nicolaides, 57 



Landois, 22, 36, 90 

Lang, 152 

Langlois, 87, 105 

La Place, 15 

Latzow, 35 

Laulani6, 16 

Lavoisier, 15 

Leathes, 148 

Le Fevre, 16 

Leschke, 28 

Leyden, 82, 87 

Lichacheff, A. A., 113, 117 

Lief man, 50 

Liebermeister, 82, 87, 110 

Liljestrand, G., 70, 71 

Limbeck, von, 155 

Linsen, 148 

Loewi, O., 68, 87 

Luedke, 157 

Lukjanow, 45 

Lusk, 142, 143 

Luthje, 50 



Page, 36 
Pari, 47 
Pettenkofer, 17 
Pflueger, 144 
Porcelli-Titone, 84 
Poulton, 148 
Prizbram, 147 
Prince, 23 

Quinqaud, 87 

Redtenbacher, 154 
Regnar, 87 
Regnard, 154 
Regnault, 16 
Reichert, 92 
Reichet, 21 
Richet, 16 
Richter, 139 
Riethus, 87 
Robitschek, 147 
Roemer, 25 



INDEX OF AUTHORS 



161 



Roily, 42, 43, 137, 138, 

141, 142, 157 
Rosenthal, C, 87 
Rosenthal, T., 87 
Roussy, 26 
Rubner, 65 
Rumford, 102 

Sachs, 19 
Sakovic, 27 
Salkowsky, 147 
Sanctorius, 17 
Sawadowsky, 52 
Schlagintiweit, 46, 51 
Schmid, 148 
Schnitzler, 25, 29 
Schultz, 137 
Sclmltze, 42, 70 
Schwartz, 155 
Schwenkenbecker, 151 
Scott, 48, 69, 71, 72, 73, 

74, 140, 153 
Senator, 82, 83, 139 
Shaffer, 147, 148 
Sharpe, 147 
Silbermann, 102 
Silberstein, 51 
Simon, 147 
Sinelnikow, 41, 46 
Smith, Robert M., 45 
Staehlin, 145, 150 



Stefani, 47 
Strassmann, 49 
Streerath, 26, 43 
Sternberg, 35 

Titone-Porcelli, 84, 85, 

86, 88 
Traube, 82, 87, 110 
Tscheschichin, 82 
Tscheschokow, 47 
Tyndall, 14 

Vaughn, 97 
Van Helmont, 14 
Virchow, 81 
Voit, 17, 32, 44 
Von der Berg, 155 
Von Limbeck, 155 
Von Noorden, 152 

Wachsmuth, 82 
Wahl, 87 
Waser, 29 
Weber, 150 
Wertheim, 87 
Weselko, 68 
White, W. Hale, 36 
Wing, 22 
Wood, H. C, 36, 92 

Zuelzer, 147 



GENEBAL INDEX 



Acetone bodies and acids 
in fever, 154 

Addison's disease, 74 

Adrenalin, Crile's state- 
ments of effects, 75 

Adrenalin, effects of injec- 
tions of, 71, 72 

Adrenalin in the blood, 
causes of increase of, 76 

Adrenals, effects of re- 
moval of, 50, 70-74 

Albumoses, effects of upon 
heat production, 96, 97 

Artificial fever experi- 
ments, 90-96 

Basedow's disease, 67 

Calorimetrical studies, 15, 
16, 24 

Calorimetry, indirect, 16, 
17 

Calorimetry of malarial 
fever, 97 

Carbon dioxide, elimina- 
tion affected by temper- 
ature of body, 27 

Carbo-hydrate metabolism, 
150 

Causes of fever, 76 



Centers of animal heat, 
14-17 

Cerebral centers, thermo- 
genic effects when ab- 
sent, 35 

Cerebral centers, control- 
ling thermotaxis, 18 

Cerebral thermogenic cen- 
ters, 22-30 

Characteristics of fever, 
155 

Chemical regulation, 44, 
47, 52, 53 

Chlorides and phosphates 
in fever, 154 

Corpora striata, effect on 
heat dissipation by re- 
moval of, 59 

Corpus striatum and ther- 
motaxis, 18, 20, 21, 22 

Corpus striatum, effects 
of local heating or cool- 
ing of, 23 

Cortical thermogenic cen- 
ters, 36-38 

Cruciate nucleus, 18 

Curarization, effects of, 
43-44 

Evaporation through 
sweat glands, 65 



163 



164 



GENERAL INDEX 



Exophthalmic goiter, 67 
Experiments determining 
thermogenic center, 19 

Faradic current, effects of 
applying to tuber cin- 
ereum, 59-60 

Fasting, effects of on tem- 
perature, 70 

Fear, a cause of fever, 76 

Fever caused by fear, 76 

Fever, destructive of bac- 
teria, 75 

Fever in man, 97 

Fever, noxious or benefi- 
cial? 157 

Fever observations, 126- 
136 

Fever-producing agents, 
84-85 

Gaseous exchange in fever, 

87, 125, 133 
Glycogen investigations, 

136 
Graves' disease, 79 

Heat, early theories as to 
source of, 14-17 

Heat dissipation through 
the skin, 65 

Heat loss by radiation and 
evaporation, 123 

Heat of animals, Lavois- 
ier's discoveries, 15 

Heat phenomena, methods 
of studying, 17 



Heat production and heat 
dissipation, 88 

Heat production and the 
spinal cord, 32 

Heat production, effected 
by partial destruction 
of spinal cord, 33 

Heat production, effects on 
of vagal section, 40-54 

Heat production in nor- 
mal conditions, 89 

Heat regulating fibers, 40 

Heat regulation and sleep, 
66 

Hyperthermia, 81-88 

Infundibulin injections, ef- 
fects of on temperature, 
69 

Iodine, effect of, 74 

Iodothyrin doses, effects 
of, 74 

Kinetic system, results of 
excessive activity of, 80 

Liver, as source of heat 
production, 42 

Malarial fever, calorimetry 
of, 97 

Malarial fever investiga- 
tions, 117 

Metabolism, first school 
for, 17 

Metabolism in fever, 136 

Metabolism of fats, 150 



GENERAL INDEX 



165 



Mid-brain thermogenic 

centers, 27-31 

Morphine, Crile's findings 
of effects of, 75, 76 

Muscle, thermogenic func- 
tion in, 45 

Myenteric plexus, effects 
of extirpation of, 70, 71 

Myxoedema, 74 

Xaphthylamine, 141 
Nerve centers controlling 

thermotaxis, 18 
Xerves thermotaxic, 38-40 
Nissl substance. 77-79 
Xitrogen and animal heat, 

15 
Xitrogen, urinary, cause 

of increase, 20 

Optic thalami, a thermo- 
genic center, 23 

Oxygen and animal heat, 
15, 16 

Oxygen, consumption of, 
16 

Peptones, effects of upon 

heat production, 96, 97 
Pituitary, effects of on 

temperature by removal, 

69 
Polypnoeic center, 57-60 
Protein destruction, causes 

of. 149 
Protein fever, 96 
Protein metabolism, 142 



Purin metabolism, 153 

Respiratory studies, 15, 16 
Rumford's compensation, 
103 

Septic fever, 98 

Shock, pathology of, 80 

Sleep, effect of on heat 
regulation, 66 

Solar plexus, effects of ex- 
tirpation of, 70, 71 

Spinal cord and C02, 32 

Spinal cord and heat pro- 
duction. 32 

Spinal cord, effect on heat 
production by partial 
destruction. 33 

Spinal cord, effect on tem- 
perature after section. 
44 

Spinal cord, thermogenic 
centers in, 32 

Splanchnics. and heat pro- 
duction, 42 

Splanchnicotomy. effects 
of, 70 

Strychnia and heat pro- 
duction. 43 

Sudorific secretion, 64 

Sugar in blood, relation of 
to temperature, 51 

Surface radiation, 65 

Sweat centers and glands, 
64 

Sylvian nucleus, 18 

Sympathetics, effects of ex- 
cision of, 48 



166 



GENERAL INDEX 



Temperature, definition of, 
88 

Thermogenesis and con- 
traction, relations of, 46 

Thermogenic function in 
muscle, 45 

Thermogenic centers, 19-23 

Thermogenic centers, clas- 
sification of, 38 

Thermogenic centers, dis- 
covery of, 19, 23 

Thermogenic centers in 
the spinal cord, 32-35 

Thermo-inhibitory centers, 
36 

Thermolysis, 57-62 

Thermotaxic fibers, 52-54 

Thermotaxic nerves, 38-40 

Thermotaxis, controlling 
nervous centers, 19 

Thyroidectomized animals, 
temperature of, 68 

Thyroids, effects on heat 
regulation by removal 
of, 68 

Titone's hypothesis on hy- 
perthermia of fever, 86 



Tuber cinereum and ther- 
motaxis, 18, 23 

Tuber cinereum, effect of 
applying faradic cur- 
rent, 59-60 

Tuber cinereum, effect on 
heat dissipation by re- 
moval of, 59 

Tuber cinereum, functions 
of, 31 

Tuber cinereum, vaso-tonic 
action of, 62 

Vagal section, effects of, 

40-54 
Vaso-tonic action of tuber 

cinereum, 62 
Visceral glands, as sources 

of heat, 41-43 

Water metabolism, 151 

Water, regulating mechan- 
ism in the animal, 27 

Watery vapor, 125 

Wood's experiments in ar- 
tificial fever, 90-96 



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7 



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SQUIER and BUGBEE— Manual of Cystoscopy. By J. 

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STEPHENSON— A Review of Hormone Therapy. 1913. 

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Number"' of the "Prescriber" (Edinburgh). 

SWIETOCHOWSKI— Mechano-Therapeutics in General 
Practice. By G. de Swietochowski, M.D'., M.R.C.S. Fel- 
low of the Royal Society of Medicine ; Clinical Assistant, 
Electrical and Massage Department King's College Hosp. 
i2mo, Cloth, xiv+141 pp., 31 Illustrations $1.50 »^. 

TURNER and PORTER— The Skiagraphy of the Acces- 
sory Nasal Sinuses. By A. Logan Turner, M.D., 
F.R.C.S.E., F.R.S.E. Surgeon to the Ear and Throat De- 
partment, The Royal Infirmary, Edinburgh, and W. G. 
Porter, M.B., B.Sc, F.R.C.S. E. Surgeon to the Eye and 
Throat Infirmary, Edinburgh. 
Quarto, Cloth, 45 pages of text. 39 plates $4-5° net. 

WANKLYN— How to Diagnose Smallpox. A Guide for 
General Practitioners, Post-Graduate Students and Others. 
By W. McC. Wanklyn, B.A., Cantab., M.R.C.S., L.R.CP., 
D.P.H. Assistant Medical Officer of the London County 
Council and formerly Medical Superintendent of the River 
Ambulance Service (Small-pox). 
8vo, Cloth, 102 pages. Illustrated $1.50 net. 

WHITE— The Pathology of Growth. Tumours. By 

Charles Powell White, M.C., F.R.C.S. Director, Pilking- 
ton Cancer Research Fund, Pathologist Christie Hospital, 
Special Lecturer in Pathology, University of Manchester. 

8vo, Cloth, xvi+235 pages. Illustrated $3-5° net. 

8 



HOEBER'S MEDICAL MOXOGRAPHS 

WATSON — Gonorrhoea and its Complications in the 
Male and Female. By David Watson, M.B., CM., Sur- 
geon Glasgow Lock Hospital, Dispensary Surgeon for Ve- 
nereal Diseases Glasgow Royal Infirmary, etc., etc. 
Cloth, 8vo., 375 pages, 72 illustrations, 12 plates, some col- 
ored $3.75 net 

WICKHAM and DEGRAIS— Radium. As employed in 
the treatment of Cancer, Angiomata. Keloids, Local Tuber- 
culosis and other affections. By Louis Wickham, M.V.O. 
Medecin de St. Lazare ; Ex-Chef de Clinique a L'Hopital 
St. Louis, and Paul Degrais, Ex-Chef de Laboratoire a 
L'Hopital St. Louis. Chefs de service au Laboratoire 
Biologique du Radium ; Laureats de L'Academie de Medi- 
cine. 
8vo, Cloth, 53 illustrations, viii+111 pp $1.25 net 

WRENCH— The Healthy Marriage. A Medical and 
Psychological Guide for Wives. By G. T. Wrench, M.D., 
B.S. Lond. Past Assistant Master of the Rotunda Hos- 
pital, Dublin. 
8vo, Cloth, x+300 pages $1.5° net 

WRIGHT— The Unexpurgated Case against Woman 
Suffrage. By Sir Almroth E. Wright, M.D.% F.R.S. 
8vo, Cloth, xii+188 pages $1.00 net 

WRIGHT — On Pharmaco-Therapy and Preventive In- 
oculation; Applied to Pneumonia in the African Native 
with a discourse on the Logical Methods which ought to be 
Employed in the Evaluation of Therapeutic Agents. By 
Sir Almroth E. Wright, M.D., F.R.S. 
Cloth, 8vo., 124 pages $1.75 ***• 

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